Pyridazin-3(2H)-one derivatives

ABSTRACT

Pyridazin-3(2H)-one derivatives of formula (I) are found to inhibit PDE-4. R 1 , R 2  and R 4  are organic radicals, R 3  is a cyclic group, and R 5  is an ester or an aryl or heteroaryl group.

This application is a national stage application under 35 U.S.C. § 371of international application number PCT/EP2003/014722, filed on Dec. 22,2003, which claims the benefit of priority from Spanish applicationnumber P200203003, filed on Dec. 26, 2002.

The present invention relates to new therapeutically usefulpyridazin-3(2H)-one derivatives, to processes for their preparation andto pharmaceutical compositions containing them. These compounds arepotent and selective inhibitors of phosphodiesterase 4 (PDE4) and arethus useful in the treatment, prevention or suppression of pathologicalconditions, diseases and disorders known to be susceptible of beingimproved by inhibition of PDE4.

Phosphodiesterases (PDEs) comprise a superfamily of enzymes responsiblefor the hydrolysis and inactivation of the second messengers cyclicadenosine monophosphate (cAMP) and cyclic guanosine monophosphate(cGMP). Eleven different PDE families have been identified to date (PDE1to PDE11) which differ in substrate preference, catalytic activity,sensitivity to endogenous activators and inhibitors, and encoding genes.

The PDE4 isoenzyme family exhibits a high affinity for cyclic AMP buthas weak affinity for cyclic GMP. Increased cyclic AMP levels caused byPDE4 inhibition are associated with the suppression of cell activationin a wide range of inflammatory and immune cells, including lymphocytes,macrophages, basophils, neutrophils, and eosinophils. Moreover, PDE4inhibition decreases the release of the cytokine Tumor Necrosis Factor α(TNFα). The biology of PDE4 is described in several recent reviews, forexample M. D. Houslay, Prog. Nucleic Acid Res. Mol. Biol. 2001, 69,249-315; J. E. Souness et al. Immunopharmacol. 2000 47, 127-162; or M.Conti and S. L. Jin, Prog. Nucleic Acid Res. Mol. Biol. 1999, 63, 1-38.

In view of these physiological effects, PDE4 inhibitors of variedchemical structures have been recently disclosed for the treatment orprevention of chronic and acute inflammatory diseases and of otherpathological conditions, diseases and disorders known to be susceptibleto amelioration by inhibition of PDE4. See, for example, U.S. Pat. Nos.5,449,686, 5,710,170, WO 98/45268, WO 99/06404, WO 01/57025, WO01/57036, WO 01/46184, WO 97/05105, WO 96/40636, U.S. Pat. Nos.5,786,354, 5,773,467, 5,753,666, 5,728,712, 5,693,659, 5,679,696,5,596,013, 5,541,219, 5,508,300, 5,502,072 or H. J. Dyke and J. G.Montana, Exp. Opin. Invest. Drugs 1999, 8, 1301-1325.

A few compounds having the capacity to selectively inhibitphosphodiesterase 4 are in active development. Examples of thesecompounds are cipamfylline (European Patent number 0 389 282 B1),arofyline (European patent number 0 435 811 B1), cilomilast, roflumilast(European Patent number 0 706 513 B1), mesopram (European Patent number0 859 766 B1) and pumafentrine (PCT Patent application number 98/21208A1).

We have now found that a novel series of pyridazin-3(2H)-one derivativesare potent and selective inhibitors of PDE4 and are therefore useful inthe treatment or prevention of these pathological conditions, diseasesand disorders, in particular asthma, chronic obstructive pulmonarydisease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritablebowel disease.

The compounds of the present invention can also be used in combinationwith other drugs known to be effective in the treatment of thesediseases. For example, they can be used in combination with steroids orimmunosuppressive agents, such as cyclosporin A, rapamycin or T-cellreceptor blockers. In this case the administration of the compoundsallows a reduction of the dosage of the other drugs, thus preventing theappearance of the undesired side effects associated with both steroidsand immunosuppressants.

Like other PDE4 inhibitors (see references above) the compounds of theinvention can also be used for blocking the ulcerogenic effects inducedby a variety of etiological agents, such as antiinflammatory drugs(steroidal or non-steroidal antiinflammatory agents), stress, ammonia,ethanol and concentrated acids. They can be used alone or in combinationwith antacids and/or antisecretory drugs in the preventive and/orcurative treatment of gastrointestinal pathologies like drug-inducedulcers, peptic ulcers, H. Pylori-related ulcers, esophagitis andgastro-esophageal reflux disease.

They can also be used in the treatment of pathological situations wheredamage to the cells or tissues is produced through conditions likeanoxia or the production of an excess of free, radicals. Examples ofsuch beneficial effects are the protection of cardiac tissue aftercoronary artery occlusion or the prolongation of cell and tissueviability when the compounds of the invention are added to preservingsolutions intended for storage of transplant organs or fluids such asblood or sperm. They are also of benefit on tissue repair and woundhealing.

Accordingly, the present invention provides novel compounds of formula(I):

wherein

R¹ and R² represent independently from each other:

-   -   a hydrogen atom;    -   a group selected from acyl, hydroxycarbonyl, alkoxycarbonyl,        carbamoyl, monoalkylcarbamoyl or di-alkylcarbamoyl;    -   an alkyl, alkenyl or alkynyl group, which is optionally        substituted by one or more, for example 1, 2, 3 or 4,        substituents selected from halogen atoms and hydroxy, alkoxy,        aryloxy, alkylthio, oxo, amino, mono- or di-alkylamino,        acylamino, carbamoyl, mono- or di-alkylcarbamoyl groups;    -   an aryl or heteroaryl group which is optionally substituted by        one or more, for example 1, 2, 3 or 4, substituents selected        from halogen atoms and hydroxy, hydroxyalkyl, hydroxycarbonyl,        alkoxy, alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy,        alkylthio, amino, nitro, cyano, mono- or di-alkylamino,        acylamino, carbamoyl, mono- or di-alkylcarbamoyl,        difluoromethyl, trifluoromethyl, difluoromethoxy or        trifluoromethoxy groups;    -   a saturated or unsaturated heterocyclic group which is        optionally substituted by one or more, for example 1, 2, 3 or 4,        substituents selected from halogen atoms and hydroxy,        hydroxyalkyl, hydroxycarbonyl, alkoxy, alkylenedioxy,        alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, oxo, amino,        nitro, cyano, mono- or di-alkylamino, acylamino, carbamoyl,        mono- or di-alkylcarbamoyl, difluoromethyl, trifluoromethyl,        difluoromethoxy or trifluoromethoxy groups;    -   a group of formula        —(CH₂)_(n)—R⁶        wherein n is an integer from 0 to 4 and R⁶ represents:    -   a cycloalkyl or cycloalkenyl group;    -   an aryl group, which is optionally substituted by one or more,        for example 1, 2, 3 or 4, substituents selected from halogen        atoms and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio,        amino, mono- or di-alkylamino, nitro, acyl, hydroxycarbonyl,        alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, cyano,        trifluoromethyl, difluoromethoxy or trifluoromethoxy groups;    -   or a 3- to 7-membered ring comprising from 1 to 4 heteroatoms        selected from nitrogen, oxygen and sulphur, which ring is        optionally substituted by one or more, for example 1, 2, 3 or 4,        substituents selected from halogen atoms and alkyl, hydroxy,        alkoxy, alkylenedioxy, amino, mono- or di-alkylamino, nitro,        cyano or trifluoromethyl groups;

R³ represents a monocyclic or polycyclic aryl or heteroaryl group, whichis optionally substituted by one or more, for example 1, 2, 3 or 4,substituents selected from

-   -   halogen atoms;    -   alkyl and alkylene groups, which are optionally substituted by        one or more, for example 1, 2, 3 or 4, substituents selected        from halogen atoms; and phenyl, hydroxy, hydroxyalkyl, alkoxy,        aryloxy, alkylthio, oxo, amino, mono- or di-alkylamino,        acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or        di-alkylcarbamoyl groups    -   phenyl, hydroxy, hydroxyalkyl, alkoxy, cycloalkoxy, nitro,        aryloxy, alkylthio, alkylsulphinyl, alkylsulphonyl,        alkylsulphamoyl, acyl, amino, mono- or di-alkylamino, acylamino,        hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or        di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido,        alkylsulphamido, aminosuphonyl, mono- or di-alkylaminosulphonyl,        cyano, difluoromethoxy, or trifluoromethoxy groups;

R⁵ represents a group —COOR⁷ or a monocyclic or polycyclic aryl orheteroaryl group, which is optionally substituted by one or more, forexample 1, 2, 3 or 4, substituents selected from:

-   -   halogen atoms;    -   alkyl and alkenyl groups, which are optionally substituted by        one or more, for example 1, 2, 3 or 4, substituents selected        from halogen atoms and phenyl, hydroxy, hydroxyalkyl, alkoxy,        aryloxy, alkylthio, oxo, amino, mono- or di-alkylamino,        acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or        di-alkylcarbamoyl groups; y    -   phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy,        alkylthio, alkylsulphinyl; alkylsulphonyl, alkylsulfamoyl,        amino, mono- or di-alkylamino, acylamino, nitro, acyl,        hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or        di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido,        alkylsulphamido, aminosuphonyl, mono- or di-alkylaminosulphonyl,        cyano, difluoromethoxy or trifluoromethoxy groups;        wherein R⁷ represents an alkyl group which is optionally        substituted by one or more, for example 1, 2, 3 or 4,        substituents selected from halogen atoms and hydroxy, alkoxy,        aryloxy, alkylthio, oxo, amino, mono- or di-alkylamino,        acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono-        or di-alkylcarbamoyl groups or a group of formula        —(CH₂)_(n)—R⁶        wherein n and R⁶ are as defined above, and

R⁴ represents:

-   -   a hydrogen atom;    -   a hydroxy, alkoxy, amino, mono- or di-alkylamino group;    -   an alkyl, alkenyl or alkynyl group which is optionally        substituted by one or more, for example 1, 2, 3 or 4,        substituents selected from halogen atoms and hydroxy, alkoxy,        aryloxy, alkylthio, oxo, amino, mono- or di-alkylamino,        acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono-        or di-alkylcarbamoyl groups;    -   or a group of formula        —(CH₂)_(n)—R⁶        wherein n and R⁶ are as defined above.

as well as the N-oxides obtainable from the heteroaryl radicals presentin the structure when these heteroradicals comprise N atoms andpharmaceutically acceptable salts thereof,

with the proviso that when R⁵ is neither an optionally substitutedheteroaryl group nor a group COOR⁷, then R³ is an optionally substitutedheteroaryl group.

Certain pyridazin-3(2H)-one derivatives of similar structure, which donot fall within the scope of the present invention, have been disclosedin J. Pharm. Sci. 1991, 80, 341-348 and J. Med. Chem. 1999, 42,1894-1900.

Further objectives of the present invention are to provide processes forpreparing said compounds; pharmaceutical compositions comprising aneffective amount of said compounds; the use of the compounds in themanufacture of a medicament for the treatment of diseases susceptible ofbeing improved by inhibition of PDE4; and methods of treatment ofdiseases susceptible to amelioration by inhibition of PDE4, whichmethods comprise the administration of the compounds of the invention toa subject in need of treatment.

As used herein the term alkyl embraces optionally substituted, linear orbranched radicals having 1 to 20 carbon atoms or, preferably 1 to 12carbon atoms. More preferably alkyl radicals are “lower alkyl” radicalshaving 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbonatoms.

Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl,t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl,1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl,1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl,3-methylpentyl and iso-hexyl radicals.

As used herein, the term alkenyl embraces optionally substituted, linearor branched, mono or polyunsaturated radicals having 1 to 20 carbonatoms or, preferably, 1 to 12 carbon atoms. More preferably alkenylradicals are “lower alkenyl” radicals having 2 to 8, preferably 2 to 6and more preferably 2 to 4 carbon atoms. In particular it is preferredthat the alkenyl radicals are mono or diunsaturated.

Examples include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl and 4-pentenylradicals.

As used herein, the term alkynyl embraces optionally substituted, linearor branched, mono or polyunsaturated radicals having 1 to 20 carbonatoms or, preferably, 1 to 12 carbon atoms. More preferably, alkynylradicals are “lower alkynyl” radicals having 2 to 8, preferably 2 to 6and more preferably 2 to 4 carbon atoms. In particular, it is preferredthat the alkynyl radicals are mono or diunsaturated.

Examples include 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and3-butynyl radicals.

When it is mentioned that alkyl, alkenyl or alkynyl radicals may beoptionally substituted it is meant to include linear or branched alkyl,alkenyl or alkynyl radicals as defined above, which may be unsubstitutedor substituted in any position by one or more substituents, for exampleby 1, 2 or 3 substituents. When two or more substituents are present,each substituent may be the same or different.

A said optionally substituted alkenyl group is typically unsubstitutedor substituted with 1, 2 or 3 substituents which may be the same ordifferent. The substituents are preferably selected from halogen atoms,preferably fluorine atoms, hydroxy groups and alkoxy groups having from1 to 4 carbon atoms. Typically, substituents on an alkenyl group arethemselves unsubstituted.

A said optionally substituted alkynyl group is typically unsubstitutedor substituted with 1, 2 or 3 substituents which may be the same ordifferent. The substituents are preferably selected from halogen atoms,preferably fluorine atoms, hydroxy groups and alkoxy groups having from1 to 4 carbon atoms. Typically, substituents on an alkynyl group arethemselves unsubstituted.

A said optionally substituted alkyl group is typically unsubstituted orsubstituted with 1, 2 or 3 substituents which may be the same ordifferent. The substituents are preferably selected from halogen atoms,preferably fluorine atoms, hydroxy groups and alkoxy groups having from1 to 4 carbon atoms. Typically, substituents on an alkyl group arethemselves unsubstituted. Preferred optionally substituted alkyl groupsare unsubstituted or substituted with 1, 2 or 3 fluorine atoms.

As used herein, the term alkylene embraces divalent alkyl moietiestypically having from 1 to 6, for example from 1 to 4, carbon atoms.Examples of C₁-C₄ alkylene radicals include methylene, ethylene,propylene, butylene, pentylene and hexylene, radicals.

A said optionally substituted alkylene group is typically unsubstitutedor substituted with 1, 2 or 3 substituents which may be the same ordifferent. The substituents are preferably selected from halogen atoms,preferably fluorine atoms, hydroxy groups and alkoxy groups having from1 to 4 carbon atoms.

When an alkylene radical is present as a substituent on another radicalit shall be deemed to be a single substituent, rather than a radicalformed by two substituents.

As used herein, the term alkoxy (or alkyloxy) embraces optionallysubstituted, linear or branched oxy-containing radicals each havingalkyl portions of 1 to 10 carbon atoms. More preferred alkoxy radicalsare “lower alkoxy” radicals having 1 to 8, preferably 1 to 6 and morepreferably 1 to 4 carbon atoms.

An alkoxy group is typically unsubstituted or substituted with 1, 2 or 3substituents which may be the same or different. The substituents arepreferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.Typically, the substituents on an alkoxy group are themselvesunsubstituted.

Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy,hydroxymethoxy, 2-hydroxyethoxy and 2-hydroxypropoxy.

As used herein, the term alkylthio embraces radicals containing anoptionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms attached to a divalent sulfur atom. More preferredalkylthio radicals are “lower alkylthio” radicals having 1 to 8,preferably 1 to 6 and more preferably 1 to 4 carbon atoms.

An alkylthio group is typically unsubstituted or substituted with 1, 2or 3 substituents which may be the same or different. The substituentsare preferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.Typically, the substituents on an alkythio group are themselvesunsubstituted.

Preferred optionally substituted alkylthio radicals include methylthio,ethylthio, n-propylthio, i-propylthio, n-butylthio, sec-butylthio,t-butylthio, trifluoromethylthio, difluoromethylthio, hydroxymethylthio,2-hydroxyethylthio and 2-hydroxypropylthio.

As used herein, the term monoalkylamino embraces radicals containing anoptionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms attached to a divalent —NH— radical. More preferredmonoalkylamino radicals are “lower monoalkylamino” radicals having 1 to8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.

A monoalkylamino group typically contains an alkyl group which isunsubstituted or substituted with 1, 2 or 3 substituents which may bethe same or different. The substituents are preferably selected fromhalogen atoms, preferably fluorine atoms, hydroxy groups and alkoxygroups having from 1 to 4 carbon atoms. Typically, the substitutents ona monoalkylamino group are themselves unsubstituted.

Preferred optionally substituted monoalkylamino radicals includemethylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino,sec-butylamino, t-butylamino, trifluoromethylamino, difluoromethylamino,hydroxymethylamino, 2-hydroxyethylamino and 2-hydroxypropylamino.

As used herein, the term dialkylamino embraces radicals containing atrivalent nitrogen atoms with two optionally substituted, linear orbranched alkyl radicals of 1 to 10 carbon atoms attached thereto. Morepreferred dialkylamino radicals are “lower dialkylamino” radicals having1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms ineach alkyl radical.

A dialkylamino group typically contains two alkyl groups, each of whichis unsubstituted or substituted with 1, 2 or 3 substituents which may bethe same or different. The substituents are preferably selected fromhalogen atoms, preferably fluorine atoms, hydroxy groups and alkoxygroups having from 1 to 4 carbon atoms. Typically, the substituents on adialkylamino group are themselves unsubstituted.

Preferred optionally substituted dialkylamino radicals includedimethylamino, diethylamino, methyl(ethyl)amino, di(n-propyl)amino,n-propyl(methyl)amino, n-propyl(ethyl)amino, di(i-propyl)amino,i-propyl(methyl)amino, i-propyl(ethyl)amino, di(n-butyl)amino,n-butyl(methyl)amino, n-butyl(ethyl)amino, n-butyl(i-propyl)amino,di(sec-butyl)amino, sec-butyl(methyl)amino, sec-butyl(ethyl)amino,sec-butyl(n-propyl)amino, sec-butyl(i-propyl)amino, di(t-butyl)amino,t-butyl(methyl)amino, t-butyl(ethyl)amino, t-butyl(n-propyl)amino,t-butyl(i-propyl)amino, trifluoromethyl(methyl)amino,trifluoromethyl(ethyl)amino, trifluoromethyl(n-propyl)amino,trifluoromethyl(i-propyl)amino, trifluoromethyl(n-butyl)amino,trifluoromethyl(sec-butyl)amino, difluoromethyl(methyl)amino,difluoromethyl(ethyl)amino, difluoromethyl(n-propyl)amino,difluoromethyl(i-propyl)amino, difluoromethyl(n-butyl))amino,difluoromethyl(sec-butyl)amino, difluoromethyl(t-butyl)amino,difluoromethyl(trifluoromethyl)amino, hydroxymethyl(methyl)amino,ethyl(hydroxymethyl)amino, hydroxymethyl(n-propyl)amino,hydroxymethyl(i-propyl)amino, n-butyl(hydroxymethyl)amino,sec-butyl(hydroxymethyl)amino, t-butyl(hydroxymethyl)amino,difluoromethyl(hydroxymethyl)amino, hydroxymethyl(trifluoromethyl)amino,hydroxyethyl(methyl)amino, ethyl(hydroxyethyl)amino,hydroxyethyl(n-propyl)amino, hydroxyethyl(i-propyl)amino,n-butyl(hydroxyethyl)amino, sec-butyl(hydroxyethyl)amino,t-butyl(hydroxyethyl)amino, difluoromethyl(hydroxyethyl)amino,hydroxyethyl(trifluoromethyl)amino, hydroxypropyl(methyl)amino,ethyl(hydroxypropyl)amino, hydroxypropyl(n-propyl)amino,hydroxypropyl(i-propyl)amino, n-butyl(hydroxypropyl)amino,sec-butyl(hydroxypropyl)amino, t-butyl(hydroxypropyl)amino,difluoromethyl(hydroxypropyl)amino, hydroxypropyl(trifluoromethyl)amino.

As used herein, the term hydroxyalkyl embraces linear or branched alkylradicals having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms,any one of which may be substituted with one or more hydroxyl radicals.

Examples of such radicals include hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxybutyl and hydroxyhexyl.

As used herein, the term alkoxycarbonyl embraces optionally substituted,linear or branched radicals each having alkyl portions of 1 to 10 carbonatoms and attached to an oxycarbonyl radical. More preferredalkoxycarbonyl radicals are “lower alkoxycarbonyl” radicals, in whichthe alkyl moiety has 1 to 8, preferably 1 to 6 and more preferably 1 to4 carbon atoms.

An alkoxycarbonyl group is typically unsubstituted or substituted with1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on an alkoxycarbonyl group arethemselves unsubstituted.

Preferred optionally substituted alkoxycarbonyl radicals includemethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl,n-butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,trifluoromethoxycarbonyl, difluoromethoxycarbonyl,hydroxymethoxycarbonyl, 2-hydroxyethoxycarbonyl and2-hydroxypropoxycarbonyl.

As used herein, the term monoalkylcarbamoyl embraces radicals containingan optionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms and attached to the nitrogen of a —NHCO— radical. Morepreferred monoalkylcarbamoyl radicals are “lower monoalkylcarbamoyl”radicals in which the alkyl moiety has 1 to 8, preferably 1 to 6 andmore preferably 1 to 4 carbon atoms.

A monoalkylcarbamoyl group is typically unsubstituted or substitutedwith 1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on a monoalkylcarbamoyl groupare themselves unsubstituted.

Preferred optionally substituted monoalkylcarbamoyl radicals includemethylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, i-propylcarbamoyl,n-butylcarbamoyl, sec-butylcarbamoyl, t-butylcarbamoyl,trifluoromethylcarbamoyl, difluoromethylcarbamoyl,hydroxymethylcarbamoyl, 2-hydroxyethylcarbamoyl and2-hydroxypropylcarbamoyl.

As used herein, the term dialkylcarbamoyl embraces radicals containing aradical NCO— where the nitrogen is attached to two optionallysubstituted, linear or branched alkyl radicals of 1 to 10 carbon atoms.More preferred dialkylcarbamoyl radicals are “lower dialkylcarbamoyl”radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4carbon atoms in each alkyl radical.

A dialkylcarbamoyl group is typically unsubstituted or substituted with1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on a dialkylcarbamoyl groupare themselves unsubstituted.

Preferred optionally substituted dialkylcarbamoyl radicals includedimethylcarbamoyl, diethylcarbamoyl, methyl(ethyl)carbamoyl,di(n-propyl)carbamoyl, n-propyl(methyl)carbamoyl,n-propyl(ethyl)carbamoyl, di(i-propyl)carbamoyl,i-propyl(methyl)carbamoyl, i-propyl(ethyl)carbamoyl,di(n-butyl)carbamoyl, n-butyl(methyl)carbamoyl, n-butyl(ethyl)carbamoyl,n-butyl(i-propyl)carbamoyl, di(sec-butyl)carbamoyl,sec-butyl(methyl)carbamoyl, sec-butyl(ethyl)carbamoyl,sec-butyl(n-propyl)carbamoyl, sec-butyl(i-propyl)carbamoyl,di(t-butyl)carbamoyl, t-butyl(methyl)carbamoyl, t-butyl(ethyl)carbamoyl,t-butyl(n-propyl)carbamoyl, t-butyl(i-propyl)carbamoyl,trifluoromethyl(methyl)carbamoyl, trifluoromethyl(ethyl)carbamoyl,trifluoromethyl(n-propyl)carbamoyl, trifluoromethyl(i-propyl)carbamoyl,trifluoromethyl(n-butyl)carbamoyl, trifluoromethyl(sec-butyl)carbamoyl,difluoromethyl(methyl)carbamoyl, difluoromethyl(ethyl)carbamoyl,difluoromethyl(n-propyl)carbamoyl, difluoromethyl(i-propyl)carbamoyl,difluoromethyl(n-butyl))carbamoyl, difluoromethyl(sec-butyl)carbamoyl,difluoromethyl(t-butyl)carbamoyl,difluoromethyl(trifluoromethyl)carbamoyl,hydroxymethyl(methyl)carbamoyl, ethyl(hydroxymethyl)carbamoyl,hydroxymethyl(n-propyl)carbamoyl, hydroxymethyl(i-propyl)carbamoyl,n-butyl(hydroxymethyl)carbamoyl, sec-butyl(hydroxymethyl)carbamoyl,t-butyl(hydroxymethyl)carbamoyl, difluoromethyl(hydroxymethyl)carbamoyl,hydroxymethyl(trifluoromethyl)carbamoyl, hydroxyethyl(methyl)carbamoyl,ethyl(hydroxyethyl)carbamoyl, hydroxyethyl(n-propyl)carbamoyl,hydroxyethyl(i-propyl)carbamoyl, n-butyl(hydroxyethyl)carbamoyl,sec-butyl(hydroxyethyl)carbamoyl, t-butyl(hydroxyethyl)carbamoyl,difluoromethyl(hydroxyethyl)carbamoyl,hydroxyethyl(trifluoromethyl)carbamoyl, hydroxypropyl(methyl)carbamoyl,ethyl(hydroxypropyl)carbamoyl, hydroxypropyl(n-propyl)carbamoyl,hydroxypropyl(i-propyl)carbamoyl, n-butyl(hydroxypropyl)carbamoyl,sec-butyl(hydroxypropyl)carbamoyl, t-butyl(hydroxypropyl)carbamoyl,difluoromethyl(hydroxypropyl)carbamoyl,hydroxypropyl(trifluoromethyl)carbamoyl.

As used herein, the term alkylsulfinyl embraces radicals containing anoptionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms attached to a divalent —SO— radical. More preferredalkylsulfinyl radicals are “lower alklsulfinyl” radicals having 1 to 8,preferably 1 to 6 and more preferably 1 to 4 carbon atoms.

An alkylsulfinyl group is typically unsubstituted or substituted with 1,2 or 3 substituents which may be the same or different. The substituentsare preferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.Typically, the substituents on a alkylsulfinyl group are themselvesunsubstituted.

Preferred optionally substituted alkylsulphinyl radicals includemethylsulphinyl, ethylsulphinyl, n-propylsulphinyl, i-propylsulphinyl,n-butylsulphinyl; sec-butylsulphinyl, t-butylsulphinyl,trifluoromethylsulphinyl, difluoromethylsulphinyl,hydroxymethylsulphinyl, 2-hydroxyethylsulphinyl and2-hydroxypropylsulphinyl.

As used herein, the term alkylsulfonyl embraces radicals containing anoptionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms attached to a divalent —SO₂— radical. More preferredalkylsulfonyl radicals are “lower alkylsulfonyl” radicals having 1 to 8,preferably 1 to 6 and more preferably 1 to 4 carbon atoms.

An alkylsulfonyl group is typically unsubstituted or substituted with 1,2 or 3 substituents which may be the same or different. The substituentsare preferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.Typically, the substituents on a monoalkylaminosulfonyl group arethemselves unsubstituted.

As used herein, the term monoalkylaminosulfonyl embraces radicalscontaining an optionally substituted, linear or branched alkyl radicalsof 1 to 10 carbon atoms and attached to the nitrogen of a —NHSO₂—radical. More preferred monoalkylaminosulfonyl radicals are “lowermonoalkylaminosulfonyl” radicals having 1 to 8, preferably 1 to 6 andmore preferably 1 to 4 carbon atoms.

A monoalkylaminosulfonyl group is typically unsubstituted or substitutedwith 1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on a monoalkylaminosulfonylgroup are themselves unsubstituted.

Preferred optionally substituted monoalkylaminosulphonyl radicalsinclude methylaminosulphonyl, ethylaminosulphonyl,n-propylaminosulphonyl, i-propylaminosulphonyl; n-butylaminosulphonyl,sec-butylaminosulphonyl, t-butylaminosulphonyl,trifluoromethylaminosulphonyl, difluoromethylaminosulphonyl,hydroxymethylaminosulphonyl, 2-hydroxyethylaminosulphonyl and2-hydroxypropylaminosulphonyl.

As used herein, the term dialkylaminosulfonyl embraces radicalscontaining a radical NSO₂— where the nitrogen is attached to twooptionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms. More preferred dialkylaminosulfonyl radicals are “lowerdialkylaminosulfonyl” radicals having 1 to 8, preferably 1 to 6 and morepreferably to 4 carbon atoms in each alkyl radical.

A dialkylaminosulfonyl group is typically unsubstituted or substitutedwith 1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on a dialkylaminosulphonylgroup are themselves unsubstituted.

Preferred optionally substituted dialkylaminosulphonyl radicals includedimethylaminosulphonyl, diethylaminosulphonyl,methyl(ethyl)aminosulphonyl, di(n-propyl)aminosulphonyl,n-propyl(methyl)aminosulphonyl, n-propyl(ethyl)aminosulphonyl,di(i-propyl)aminosulphonyl, i-propyl(methyl)aminosulphonyl,i-propyl(ethyl)aminosulphonyl, di(n-butyl)aminosulphonyl,n-butyl(methyl)aminosulphonyl; n-butyl(ethyl)aminosulphonyl,n-butyl(i-propyl)aminosulphonyl, di(sec-butyl)aminosulphonyl,sec-butyl(methyl)aminosulphonyl, sec-butyl(ethyl)aminosulphonyl,sec-butyl(n-propyl)aminosulphonyl, sec-butyl(i-propyl)aminosulphonyl,di(t-butyl)aminosulphonyl, t-butyl(methyl)aminosulphonyl,t-butyl(ethyl)aminosulphonyl, t-butyl(n-propyl)aminosulphonyl,t-butyl(i-propyl)aminosulphonyl, trifluoromethyl(methyl)aminosulphonyl,trifluoromethyl(ethyl)aminosulphonyl,trifluoromethyl(n-propyl)aminosulphonyl,trifluoromethyl(i-propyl)aminosulphonyl,trifluoromethyl(n-butyl)aminosulphonyl,trifluoromethyl(sec-butyl)aminosulphonyl,difluoromethyl(methyl)aminosulphonyl,difluoromethyl(ethyl)aminosulphonyl,difluoromethyl(n-propyl)aminosulphonyl,difluoromethyl(i-propyl)aminosulphonyldifluoromethyl(n-butyl))aminosulphonyl,difluoromethyl(sec-butyl)aminosulphonyl,difluoromethyl(t-butyl)aminosulphonyl,difluoromethyl(trifluoromethyl)aminosulphonyl,hydroxymethyl(methyl)aminosulphonyl, ethyl(hydroxymethyl)aminosulphonyl,hydroxymethyl(n-propyl)aminosulphonyl,hydroxymethyl(i-propyl)aminosulphonyl,n-butyl(hydroxymethyl)aminosulphonyl,sec-butyl(hydroxymethyl)aminosulphonyl,t-butyl(hydroxymethyl)aminosulphonyl,difluoromethyl(hydroxymethyl)aminosulphonyl,hydroxymethyl(trifluoromethyl)aminosulphonyl,hydroxyethyl(methyl)aminosulphonyl, ethyl(hydroxyethyl)aminosulphonyl,hydroxyethyl(n-propyl)aminosulphonyl,hydroxyethyl(i-propyl)aminosulphonyl,n-butyl(hydroxyethyl)aminosulphonyl,sec-butyl(hydroxyethyl)aminosulphonyl;t-butyl(hydroxyethyl)aminosulphonyl,difluoromethyl(hydroxyethyl)aminosulphonyl,hydroxyethyl(trifluoromethyl)aminosulphonyl,hydroxypropyl(methyl)aminosulphonyl, ethyl(hydroxypropyl)aminosulphonyl,hydroxypropyl(n-propyl)aminosulphonyl,hydroxypropyl(i-propyl)aminosulphonyl,n-butyl(hydroxypropyl)aminosulphonyl,sec-butyl(hydroxypropyl)aminosulphonyl,t-butyl(hydroxypropyl)aminosulphonyl,difluoromethyl(hydroxypropyl)aminosulphonyl andhydroxypropyl(trifluoromethyl)aminosulphonyl.

As used herein, the term alkylsulfamoyl embraces radicals containing anoptionally substituted, linear or branched alkyl radical of 1 to 10carbon atoms and attached to the nitrogen of a —NSO₂— radical. Morepreferred alkylsulfamoyl radicals are “lower alkylsulfamoyl” radicalshaving 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbonatoms.

An alkylsulphamoyl group is typically unsubstituted or substituted with1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on an alkylsulphamoyl groupare themselves unsubstituted.

Preferred optionally substituted alkylsulfamoyl radicals includemethylsulphamoyl, ethylsulphamoyl, n-propylsulphamoyl,i-propylsulphamoyl, n-butylsulphamoyl, sec-butylsulphamoyl,t-butylsulphamoyl, trifluoromethylsulphamoyl, difluoromethylsulphamoyl,hydroxymethylsulphamoyl, 2-hydroxyethylsulphamoyl and2-hydroxypropylsulphamoyl.

As used herein, the term alkylsulphamido embraces radicals containing anoptionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms and attached to one of the nitrogen atoms of a —NHSO₂NH—radical. More preferred alkylsulphamido radicals are “loweralkylsulphamido” radicals having 1 to 8, preferably 1 to 6 and morepreferably 1 to 4 carbon atoms.

An alkylsulphamido group is typically unsubstituted or substituted with1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on an alkylsulphamido groupare themselves unsubstituted.

Preferred optionally substituted alkylsulphamido radicals includemethylsulphamido, ethylsulphamido, n-propylsulphamido,i-propylsulphamido, n-butylsulphamido, sec-butylsulphamido,t-butylsulphamido, trifluoromethylsulphamido, difluoromethylsulphamido,hydroxymethylsulphamido, 2-hydroxyethylsulphamido and2-hydroxysulphamido.

As used herein, the term N′-alkylureido embraces radicals containing anoptionally substituted, linear or branched alkyl radical of 1 to 10carbon atoms attached to the terminal nitrogen of a —NHCONH— radical.More preferred N′-alkylureido radicals are “lower N′-alkylureido”radicals in which the alkyl moiety has 1 to 8, preferably 1 to 6 andmore preferably 1 to 4 carbon atoms.

An N′-alkylureido group is typically unsubstituted or substituted with1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on an N′-alkylureido group arethemselves unsubstituted.

Preferred optionally substituted N′-alkylureido radicals includeN′-methylureido, N′-ethylureido, N′-n-propylureido, N′-i-propylureido,N′-n-butylureido, N′-sec-butylureido, N′-t-butylureido,N′-trifluoromethylureido, N′-difluoromethylureido,N′-hydroxymethylureido, N′-2-hydroxyethylureido andN′-2-hydroxypropylureido.

As used herein, the term N′,N′-dialkylureido embraces radicalscontaining a radical—NHCON where the terminal nitrogen is attached totwo optionally substituted, linear or branched alkyl radicals of 1 to 10carbon atoms. More preferred N′,N′-dialkylureido radicals are “lowerN′,N′-dialkylureido” radicals-having 1 to 8, preferably 1 to 6 and morepreferably 1 to 4 carbon atoms in each alkyl radical.

A N′,N′-dialkylureido group is typically unsubstituted or substitutedwith 1, 2 or 3 substituents which may be the same or different. Thesubstituents are preferably selected from halogen atoms, preferablyfluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4carbon atoms. Typically, the substituents on an N′,N′-dialkylureidogroup are themselves unsubstituted.

Preferred optionally substituted N′,N′-dialkylureido radicals includeN′,N′-dimethylureido, N′,N′-diethylureido, N′-methyl, N′-ethylureido,N′,N′-di(n-propyl)ureido, N′-n-propyl, N′-methylureido, N′-n-propyl,N′-ethylureido, N′,N′-di(i-propyl)ureido, N′-i-propyl, N′-methylureido,N′-1-propyl, N′-ethylureido, N′,N′-di(n-butyl)ureido, N′-n-butyl,N′-methylureido, N′-n-butyl, N′-ethylureido, N′-n-butyl,N′-(i-propyl)ureido, N′,N′-di(sec-butyl)ureido, N′-sec-butyl,N′-methylureido, N′-sec-butyl, N′-ethylureido, N′-sec-butyl,N′-(n-propyl)ureido, N′-sec-butyl, N′(i-propyl)ureido,N′,N′di(t-butyl)ureido, N′-t-butyl, N′-methylureido, N′-t-butyl,N′-ethylureido, N′-t-butyl, N′-(n-propyl)ureido, N′-t-butyl,N′-(i-propyl)ureido, N′-trifluoromethyl, N′-methylureido,N′-trifluoromethyl, N′-ethylureido, N′-trifluoromethyl,N′-(n-propyl)ureido, N′-trifluoromethyl, N′-(i-propyl)ureido,N′-trifluoromethyl, N′-(n-butyl)ureido, N′-trifluoromethyl,N′-(sec-butyl)ureido, N′-difluoromethyl, N′-methylureido,N′-difluoromethyl, N′-ethylureido, N′-difluoromethyl,N′(n-propyl)ureido, N′-difluoromethyl, N′-(i-propyl)ureido,N′-difluoromethyl, N′-(n-butyl)ureido, N′-difluoromethyl,N′-(sec-butyl)ureido, N-difluoromethyl, N′-(t-butyl)ureido,N′-difluoromethyl, N′-trifluoromethylureido, N′-hydroxymethyl,N′-methylureido, N′-ethyl, N′-hydroxymethylureido, N′-hydroxymethyl,N′-(n-propyl)ureido, N′-hydroxymethyl, N′-(i-propyl)ureido, N′-n-butyl,N′-hydroxymethylureido, N′-sec-butyl, N′-hydroxymethylureido,N′-t-butyl, N′-hydroxymethylureido, N′-difluoromethyl,N′-hydroxymethylureido, N′-hydroxymethyl, N′-trifluoromethylureido,N′-hydroxyethyl, N′-methylureido, N′-ethyl, N′-hydroxyethylureido,N′-hydroxyethyl, N′-(n-propyl)ureido, N′-hydroxyethyl,N′-(i-propyl)ureido, N′-(n-butyl), N′-hydroxyethylureido, N′(sec-butyl),N′-hydroxyethylureido, N′-(t-butyl), N′-hydroxyethylureido,N′-difluoromethyl, N′-hydroxyethylureido, N′-hydroxyethyl,N′-trifluoromethylureido, N′-hydroxypropyl, N′-methylureido, N′-ethyl,N′-hydroxypropylureido, N′-hydroxypropyl, N′-(n-propyl)ureido,N′-hydroxypropyl, N′-(i-propyl)ureido, N′-(n-butyl),N′-hydroxypropylureido, N′(sec-butyl), N′-hydroxypropylureido,N′(t-butyl), N′-hydroxypropylureido, N′-difluoromethyl,N′-hydroxypropylureido y N′-hydroxypropyl, N′-trifluoromethylureido.

As used herein, the term acyl embraces optionally substituted, linear orbranched radicals having 2 to 20 carbon atoms or, preferably 2 to 12carbon atoms attached to a carbonyl radical. More preferably acylradicals are “lower acyl” radicals of formula—COR, wherein R is ahydrocarbon group, preferably an alkyl group, having 2 to 8, preferably2 to 6 and more preferably 2 to 4 carbon atoms.

An acyl group is typically unsubstituted or substituted with 1, 2 or 3substituents which may be the same or different. The substituents arepreferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.Typically, the substituents on an acyl group are themselvesunsubstituted.

Preferred optionally substituted acyl radicals include acetyl,propionyl, butiryl, isobutiryl, isovaleryl, pivaloyil, valeryl, lauryl,myristyl, stearyl and palmityl,

As used herein, the term aryl radical embraces typically a C₅-C₁₄monocyclic or polycyclic aryl radical such as phenyl, naphthyl,anthranyl and phenanthryl. Phenyl is preferred.

A said optionally substituted aryl radical is typically unsubstituted orsubstituted with 1, 2 or 3 substituents which may be the same ordifferent. The substituents are preferably selected from halogen atoms,preferably fluorine atoms, hydroxy groups, alkoxycarbonyl groups inwhich the alkyl moiety has from 1 to 4 carbon atoms, hydroxycarbonylgroups, carbamoyl groups, nitro groups, cyano groups, C₁-C₄ alkylgroups, C₁-C₄ alkoxy groups and C₁-C₄ hydroxyalkyl groups. When an arylradical carries 2 or more substituents, the substituents may be the sameor different. Unless otherwise specified, the substituents on an arylgroup are typically themselves unsubstituted.

As used herein, the term heteroaryl radical embraces typically a 5- to14-membered ring system, preferably a 5- to 10-membered ring system,comprising at least one heteroaromatic ring and containing at least oneheteroatom selected from O, S and N. A heteroaryl radical may be asingle ring or two or more fused rings wherein at least one ringcontains a heteroatom.

A said optionally substituted heteroaryl radical is typicallyunsubstituted or substituted with 1, 2 or 3 substituents which may bethe same or different. The substituents are preferably selected fromhalogen atoms, preferably fluorine, chlorine or bromine atoms,alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbonatoms, nitro groups, hydroxy groups, C₁-C₄ alkyl groups and C₁-C₄ alkoxygroups. When an heteroaryl radical carries 2 or more substituents, thesubstituents may be the same or different. Unless otherwise specified,the substituents on a heteroaryl radical are typically themselvesunsubstituted.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl,benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl,imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl,pyridinyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl,isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl,isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl,pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl,thieno[2,3-d]pyrimidnyl and the various pyrrolopyridyl radicals.

The mention of optionally substituted heteroaryl radicals or restswithin the present invention is intended to cover the N-oxidesobtainable from these radicals when they comprise N-atoms.

Oxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl,thiadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl,benzoxazolyl, naphthyridinyl, benzofuranyl, pyrazinyl, pyrimidinyl andthe various pyrrolopyridyl radicals are preferred.

As used herein, the term cycloalkyl embraces saturated carbocyclicradicals and, unless otherwise specified, a cycloalkyl radical typicallyhas from 3 to 7 carbon atoms.

A cycloalkyl radical is typically unsubstituted or substituted with 1, 2or 3 substituents which may be the same or different. The substituentsare preferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. When acycloalkyl radical carries 2 or more substituents, the substituents maybe the same or different. Typically the substituents on a cycloalkylgroup are themselves unsubstituted.

Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. It is preferably cyclopropyl, cyclopentyl and cyclohexyl.

As used herein, the term cycloalkenyl embraces partially unsaturatedcarbocyclic radicals and, unless otherwise specified, a cycloalkenylradical typically has from 3 to 7 carbon atoms.

A cycloalkenyl radical is typically unsubstituted or substituted with 1,2 or 3 substituents which may be the same or different. The substituentsare preferably selected from halogen atoms, preferably fluorine atoms,hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. When acycloalkenyl radical carries 2 or more substituents, the substituentsmay be the same or different. Typically, the substituents on acycloalkenyl group are themselves unsubstituted.

Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl andcycloheptenyl. Cyclopentenyl and cyclohexenyl are preferred.

As used herein, the term heterocyclyl radical embraces typically anon-aromatic, saturated or unsaturated C₃-C₁₀ carbocyclic ring, such asa 5, 6 or 7 membered radical, in which one or more, for example 1, 2, 3or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms arereplaced by a heteroatom selected from N, O and S. Saturatedheterocyclyl radicals are preferred. A heterocyclic radical may be asingle ring or two or more fused rings wherein at least one ringcontains a heteroatom. When a heterocyclyl radical carries 2 or moresubstituents, the substituents may be the same or different.

A said optionally substituted heterocyclyl radical is typicallyunsubstituted or substituted with 1, 2 or 3 substituents which may bethe same or different. The substituents are preferably selected fromhalogen atoms, preferably fluorine atoms, hydroxy groups and alkoxygroups having from 1 to 4 carbon atoms. Typically, the substituents on aheterocyclyl radical are themselves unsubstituted.

Examples of heterocyclic, radicals include piperidyl, pyrrolidyl,pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl,pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl,tetrazolyl, cromanyl, isocromanyl, imidazolidinyl, imidazolyl, oxiranyl,azaridinyl, 4,5-dihydro-oxazolyl and 3-aza-tetrahydrofuranyl.

Where a heterocyclyl radical carries 2 or more substituents, thesubstituents may be the same or different.

As used herein, some of the atoms, radicals, moieties, chains and cyclespresent in the general structures of the invention are “optionallysubstituted”. This means that these atoms, radicals, moieties, chainsand cycles can be either unsubstituted or substituted in any position byone or more, for example 1, 2, 3 or 4, substituents, whereby thehydrogen atoms bound to the unsubstituted atoms, radicals, moieties,chains and cycles are replaced by chemically acceptable atoms, radicals,moieties, chains and cycles. When two or more substituents are present,each substituent may be the same or different. The substituents aretypically themselves unsubstituted.

Typically when a cyclic radical is bridged by an alkylene oralkylenedioxy radical, the bridging alkylene radical is attached to thering at non-adjacent atoms.

As used herein, the term halogen atom embraces chlorine, fluorine,bromine and iodine atoms. A halogen atom is typically a fluorine,chlorine or bromine atom, most preferably chlorine or fluorine. The termhalo when used as a prefix has the same meaning.

As used herein, an acylamino group is typically a said acyl groupattached to an amino group.

As used herein an alkylenedioxy group is typically —O—R—O—, wherein R isa said alkylene group.

As used herein, an alkoxyacyl group is typically a said alkoxy groupattached to a said acyl group.

As used herein, an acyloxy group is typically a said acyl group attachedto an oxygen atom.

As used herein, a cycloalkoxy group is typically a said cycloalkyl groupattached to an oxygen atom.

Compounds containing one or more chiral centre may be used inenantiomerically or diastereoisomerically pure form, or in the form of amixture of isomers.

As used herein, the term pharmaceutically acceptable salt embraces saltswith a pharmaceutically acceptable acid or base. Pharmaceuticallyacceptable acids include both inorganic acids, for example hydrochloric,sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitricacid and organic acids, for example citric, fumaric, maleic, malic,mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic,methanesulphonic, ethanesulphonic, benzenesulphonic orp-toluenesulphonic acid. Pharmaceutically acceptable bases includealkali metal (e.g. sodium or potassium) and alkali earth metal (e.g.calcium or magnesium) hydroxides and organic bases, for example alkylamines, arylalkyl amines and heterocyclic amines.

According to one embodiment of the present invention in the compounds offormula (I) R² represents a hydrogen atom or an aryl group, for examplea phenyl group, which is optionally substituted by one or more, forexample 1, 2, 3 or 4, substituents selected from halogen atoms andnitro, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl and —CO₂—(C₁-C₄ alkyl) groups.More preferably, R² is a hydrogen-atom or a phenyl group which isunsubstitued or substituted with 1 or 2 unsubstituted substituentsselected from fluorine, chlorine, nitro, C₁-C₄ hydroxyalkyl and—CO₂—(C₁-C₂ alkyl) substituents. Most preferably R² is hydrogen.

In another embodiment of the present invention in the compounds offormula (I) R¹ represents a group selected from:

-   -   a (C₁₋₄) alkyl group which is optionally substituted by one or        more, for example 1, 2, 3 or 4 hydroxy groups;    -   a group of formula        —(CH₂)_(n)—R⁶        wherein n is an integer from 1 to 3 and R⁶ represents a (C₃₋₆)        cycloalkyl group.

More preferably, R¹ is an unsubstituted C₁-C₄ alkyl, an unsubstitutedC₁-C₄ hydroxyalkyl or an unsubstituted cyclopropyl-(C₁-C₄ alkyl)-group.

In still another embodiment of the present invention in the compounds offormula (I) R³ represents a group selected from monocyclic or polycyclicaryl or heteroaryl groups, which are optionally substituted by one ormore, for example 1, 2, 3 or 4, substituents selected from:

-   -   halogen atoms;    -   (C₁-C₄) alkyl groups, which are optionally substituted by one or        more, for example 1, 2, 3 or 4 hydroxy groups;    -   and (C₁-C₄) alkoxy, nitro, hydroxy, hydroxycarbonyl, carbamoyl,        (C₁-C₄ alkoxy)-carbonyl and cyano groups

In another embodiment of the present invention in the compounds offormula (I), R³ represents a monocyclic or polycyclic aryl or heteroarylgroup, which is optionally substituted by one or more, for example 1, 2,3 or 4, substituents selected from:

-   -   halogen atoms;    -   alkyl and alkylene groups, which are optionally substituted by        one or more, for example 1, 2, 3 or 4, substituents selected        from halogen atoms; and    -   phenyl, hydroxy, hydroxycarbonyl, hydroxyalkyl, alkoxycarbonyl,        alkoxy, cycloalkoxy, nitro, aryloxy, alkylthio, alkylsulphinyl,        alkylsulphonyl, alkylsulphamoyl, acyl, amino, mono- or        di-alkylamino, acylamino hydroxycarbonyl, alkoxycarbonyl,        carbamoyl, mono- or di-alkylcarbamoyl, ureido, N′-alkylureido,        N′,N′-dialkylureido, alkylsulphamido, aminosulphonyl, mono- or        di-alkylaminosulphonyl, cyano, difluoromethoxy or        trifluoromethoxy groups;

More preferably, R³ represents a phenyl group, a naphthyl group or a 5-to 14-membered monocylic or polycyclic heteroaryl group containing 1, 2or 3 heteroatoms selected from N, O and S, the phenyl, naphthyl andheteroaryl groups being unsubstituted or substituted with 1 or 2unsubstituted substituents selected from:

-   -   halogen atoms, for example fluorine and chlorine atoms;    -   C₁-C₄ alkyl and C₁-C₄ hydroxyalkyl groups; and    -   C₁-C₄ alkoxy, nitro, hydroxy, hydroxycarbonyl, carbamoyl, (C₁-C₄        alkoxy)-carbonyl and cyano groups.

Still more preferably R³ represents a phenyl group, a naphtyl group or asubstituted or unsubstituted heteroaryl group selected from substitutedor unsubstituted oxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl,thiazolyl, thiadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl,indolyl, benzoxazolyl, naphthyridinyl, benzofuranyl, pyrazinyl,pyrimidinyl and the various pyrrolopyridyl radicals.

In another embodiment of the present invention in the compounds offormula (I) R⁴ represents

-   -   an unsubstituted mono-(C₁-C₄ alkyl)amino or di-(C₁-C₄        alkyl)amino group;    -   a C₁-C₄ alkyl group which is unsubstituted or substituted by one        or more, for example 1 or 2, substituents selected from hydroxy,        C₁-C₄ alkoxy, amino, mono-(C₁-C₄ alkyl)amino and di-(C₁-C₄        alkyl)amino groups;    -   an unsubstituted phenyl-(C₁-C₄ alkyl)-group; or    -   a group of formula        —(CH₂)_(n)—R⁶        wherein n is 2 and R⁶ represents a radical selected from phenyl,        pyridyl and thienyl optionally substituted by one or more        substituents selected from halogen atoms and alkyl, hydroxy,        alkoxy, alkylenedioxy, amino, mono- or di-alkylamino, nitro,        ciano and trifluoromethyl groups.

More preferably, R⁴ represents an alkyl group having from 1 to 6 carbonatoms and which is unsubstituted or substituted by one or more, forexample 1, 2, 3 or 4, substituents selected from halogen atoms andhydroxy groups.

In yet another embodiment of the present invention in the compounds offormula (I) R⁵ represents a group COOR⁷ or a monocyclic or polycyclicaryl or heteroaryl group, which is optionally substituted by one or moresubstituents selected from halogen atoms, C₁-C₄ alkyl groups, C₁-C₄alkoxycarbonyl groups, a hydroxycarbonyl group and C₁-C₄ alkoxy groups,wherein R⁷ is as defined above.

In another preferred embodiment of the present invention in thecompounds of formula (I) R⁵ represents a group —COOR⁷ or a monocyclic orpolycyclic aryl or heteroaryl group, which is optionally substituted byone or more, for example 1, 2, 3 or 4, substituents selected fromhalogen atoms and C₁-C₄ alkoxy groups, wherein R⁷ has the meaningdefined above.

More preferably, R⁵ represents —CO₂R⁷, wherein R⁷ represents anunsubstituted C₁-C₄ alkyl group, or R₅ represents a phenyl group or a 5-to 10-membered monocyclic or polycyclic heteroaryl group containing 1 or2 heteroatoms selected from N, O and S, the phenyl and heteroaryl groupsbeing unsubstituted or substituted by 1 or 2 substituents selected fromC₁-C₄ alkoxy groups and halogen atoms, for example chlorine and fluorineatoms.

Still more preferably R⁵ represents a phenyl group, or a substituted orunsubstituted heteroaryl group selected from substituted orunsubstituted oxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl,thiazolyl, thiadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl,indolyl, benzoxazolyl, naphthyridinyl, benzofuranyl, pyrazinyl,pyrimidinyl and the various pyrrolopyridyl radicals.

Finally in another embodiment of the present invention, when R⁵represents a polycyclic heteroaryl group it is typically a group offormula (XXIII):

wherein Y represents an O atom, a S atom or a —NH— group, n is 0, 1 or 2and each R is the same or different and is a halogen atom or a C₁-C₄alkoxy group.

Particular individual compounds of the invention include:

-   5-acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3,5-dichlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-3-ylpyridazin-3(2H)-one-   methyl    4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzoate-   5-acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-3-ylpyridazin-3(2H)-one-   3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   3-{[5-acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   methyl    4-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl]amino}benzoate-   5-acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-2-ylpyridazin-3(2H)-one-   3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one-   3-{[5-acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-2-ylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyridin-2-ylpyridazin-3(2H)-one-   3-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   5-acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3,5-dichlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one-   5-acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   methyl    4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoate-   5-acetyl-2-ethyl-4-[(2-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one-   4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoic    acid-   5-acetyl-2-(cyclopropylmethyl)-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   3-{[5-acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   5-acetyl-2-(cyclopropylmethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   3-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   5-acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis-(4-methoxycarbonylphenyl)-amino]-2    ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-{bis[4-(hydroxymethyl)phenyl]amino}-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-nitrophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3,5-dichlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(4-methoxycarbonylphenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-4-[(3,5-dichloropyridin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(pyrazin-2-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(pyrimidin-2-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(5-nitropyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1h-indol-4-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-(1,3-benzothiazol-6-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(thianthren-1-ylamino)pyridazin-3(2H)-one-   methyl    3-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylate-   5-acetyl-2-ethyl-4-[(4-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(1h-1,2,4-triazol-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(6-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(2H-indazol-5-ylamino)-6-phenylpyridazin-3(2H)-one-   methyl    4-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-3-carboxylate-   5-acetyl-2-ethyl-6-phenyl-4-(pyridin-2-ylamino)pyridazin-3(2H)-one-   3-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylic    acid-   5-acetyl-2-ethyl-4-[(3-methylcinnolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4[(2-methylquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1h-indol-5-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-5-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(6-methoxyquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(5-bromoquinolin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(4-methylpyrimidin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-(cyclopropylmethyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-6-(3-fluorophenyl)-2-isopropyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-6-(1h-benzimidazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one-   5-acetyl-6-(1,3-benzoxazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one-   5-acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)one-   5-acetyl-6-benzooxazol-2-yl-4-[bis-(3-chlorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one-   5-acetyl-6-benzooxazol-2-yl-4-[bis-(3-fluorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one-   3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzamide-   5-acetyl-2-ethyl-4-(isoquinolin-1-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(2-butylquinazolin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-(1,2-benzisothiazol-3-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-hydroxy-7h-purin-6-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(quinazolin-4-ylamino)pyridazin-3(2H)-one-   5-acetyl-4-[(4-chloro-1H-indazol-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(7-chloroquinolin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(4,6-dichloropyrimidin-2-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(6-hydroxy-2H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-methylquinolin-4-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1H-imidazol-2-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(quinolin-4-ylamino)pyridazin-3(2H)-one-   5-acetyl-4-(cinnolin-4-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-d]pyrimidin-4-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1H-indazol-6-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-(6-methoxypyridin-3-yl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-thien-3-ylpyridazin-3(2H)one-   5-acetyl-6-(1-benzofuran-5-yl)-2-ethyl-4[(3-fluorophenyl)amino]pyridazin-3(2H)-one-   1-ethyl-5-[(3-methoxyphenyl)amino]-n,n-dimethyl-6-oxo-3-pyridin-3-yl-1,6-dihydropyridazine-4-carboxamide-   5-[(3-chlorophenyl)amino]-1-ethyl-n-methyl-6-oxo-3-pyridin-4-yl-1,6-dihydropyridazine-4-carboxamide-   2-ethyl-4-[(3-fluorophenyl)amino]-5-glycoloyl-6-pyridin-4-ylpyridazin-3(2H)-one-   2-ethyl-4-[(3-fluorophenyl)amino]-5-(methoxyacetyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-[(dimethylamino)acetyl]-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   2-ethyl-4-[(3-fluorophenyl)amino]-5-[(methylamino)acetyl]-6-pyridin-4-ylpyridazin-3(2H)-one-   3-{[2-ethyl-3-oxo-5-(3-phenylpropanoyl)-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzamide-   ethyl    4-acetyl-5-[(3-chlorophenyl)amino]-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate-   ethyl    4-acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate-   5-acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1,6-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(5-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-pyridin-4-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-pyridin-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-pyridin-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one-   4-[(5-acetyl-2-ethyl-3-oxo-6-thien-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   5-acetyl-2-ethyl-6-thien-2-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one-   5-Acetyl-4-(bis(4-cyanophenyl)amino)-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-4-(quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(quinolin-5-ylamino)-6-thien-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-3-ylpyridazin-3(2H)-one-   4-[(5-acetyl-2-ethyl-3-oxo-6-thien-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   5-acetyl-2-ethyl-6-thien-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one-   2-ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   2-ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   2-ethyl-4-(isoquinolin-4-ylamino)-6-phenyl-5-(3-phenylpropanoyl)pyridazin-3(2H)-one-   2-ethyl-6-phenyl-4-(quinolin-5-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one-   2-ethyl-6-phenyl-4-(pyridin-3-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one-   5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(1H-imidazo[4,5-b]pyridin-2-yl)pyridazin-3(2H)-one-   5-acetyl-6-(1,3-benzothiazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one-   5-acetyl-6-(1-benzofuran-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-pyridin-3-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzoic    acid-   5-acetyl-2-ethyl-4-[(1-oxidopyridin-3-yl)amino]-6-phenylpyridazin-3(2H)one-   ethyl    3-(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-ylamino)benzoate-   3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzamide-   5-acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-b]pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(6-fluoropyridin-3-yl)-amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-{[2-(dimethylamino)pyridin-3-yl]amino}-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridine-2-carboxylic-acid-   5-acetyl-2-ethyl-4-[(2-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1H-indazol-4-ylamino)-6-phenylpyridazin-3(2H)one-   5-acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinamide-   5-acetyl-2-ethyl-4-(1,7-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one-   2-ethyl-5-glycoloyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   methyl    5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinic    acid-   5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinic    acid-   5-acetyl-2-ethyl-4-(1,5-naphthyridin-3-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(8-hydroxy-1,7-naphthyridin-5-yl)amino]6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(thien-2-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-[(2-phenylpyridin-3-yl)amino]pyridazin-3(2H)-one-   ethyl    {5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridin-2-yl}acetate-   5-acetyl-2-ethyl-4-[(6-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(6-hydroxypyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-fluoropyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(6-chloro-4-methylpyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(3-hydroxypyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4[(4-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-8-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(quinolin-7-ylamino)pyridazin-3(2H)-one-   5-acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-4-[(2-chloropyridin-3-yl)amino]-2-(cyclopropylmethyl)-6-(4-fluorophenyl)pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(pyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-4-[(2-chloropyridin-3-yl)amino]-2-ethylpyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   methyl    5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-8-carboxylate-   5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methoxyphenyl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methoxy-phenyl)-4-(1-oxy-quinolin-5-ylamino)-2H-pyridazin-3-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methoxyphenyl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methylphenyl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methylphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methylphenyl)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   methyl    4-[4-acetyl-1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl]benzoate-   methyl    4-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate-   4-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoic    acid-   methyl    4-{4-acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}benzoate-   4-{4-acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}benzoic    acid-   methyl    3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate-   3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoic    acid-   5-acetyl-4-[(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   5-acetyl-4-[(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   5-acetyl-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   methyl    [4-acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetate-   [4-acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetic    acid-   5-acetyl-2-ethyl-4-[(3-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)one-   5-acetyl-2-ethyl-6-phenyl-4-(1H-pyrazol-3-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-phenyl-4-(9H-purin-6-ylamino)pyridazin-3(2H)one-   5-acetyl-2-ethyl-4-[(3-methylisoxazol-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(8-hydroxyquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(1H-indazol-7-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-4-[(6-bromoquinolin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(5-methylisoxazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-(isoxazol-3-ylamino)-6-phenylpyridazin-3(2H)-one-   5-acetyl-2    (cyclopropylmethyl)-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(1-methyl-1H-pyrazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-oxidoisoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-pyridin-4-yl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-pyridin-3-yl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(8-fluoroquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-(quinolin-8-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-(quinolin-8-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-4-[(2-methylquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one-   5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(isoquinolin-5-ylamino)    pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one-   5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-8-carboxylic    acid    and pharmaceutically acceptable salts thereof.

Of outstanding interest are:

-   5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-3-ylpyridazin-3(2H)-one-   5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one-   5-Acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   5-Acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   4[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoic    acid-   5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one-   5-Acetyl-2-ethyl-6-phenyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-Acetyl-2-ethyl-6-phenyl-4-quinolin-8-ylamino)pyridazin-3(2H)-one-   5-Acetyl-2-ethyl-4-(1H-indol-4-ylamino)-6-phenylpyridazin-3(2H)-one-   5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one-   5-Acetyl-6-(3-fluorophenyl)-2-isopropyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-Acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   5-Acetyl-2-ethyl-4-(isoquinolin-5-ylamino)-6-phenylpyridazin-3(2H)-one-   5-Acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one    and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared by one of theprocesses described below.

Compounds (I) may be obtained as shown in Scheme 1.

An isoxazolo[3,4-d]pyridazin-7(6H)-one of formula (II), wherein R¹, R⁴and R⁵ are as hereinbefore defined, is hydrogenated to yield an4-aminopyridazin-3(2H)-one derivative (III), wherein R¹, R⁴ and R⁵ areas hereinbefore defined. The hydrogenation may be performed using forexample hydrogen in the presence of a catalyst by methods known per se,e.g. V. Dal Piaz et al. Heterocycles, 1991, 32, 1173. Alternatively, thereaction may be accomplished by transfer hydrogenation using an organichydrogen donor and a transfer agent, such as ammonium formate orhydrazine by methods known per se, e.g. V. Dal Piaz et al. Heterocycles,1991, 32, 1173.

Condensation of 4-aminopyridazin-3(2H)-ones (III) with an aryl orheteroaryl bromide of formula (A) wherein R³ is as hereinbefore defined,gives compounds (Ia), wherein R¹, R³, R⁴ and R⁵ are as hereinbeforedefined. The reaction is carried out in the presence of a copper saltsuch as cuprous iodide and an inorganic base such as potassiumphosphate, potassium carbonate or sodium carbonate and can also beperformed in the presence of an organic base, preferably a diamine basesuch as N,N′-dimethylethylenediamine in an inert solvent such astoluene, dioxane or dimethylformamide, at a temperature from −20° C. tothe boiling point of the solvent. It can also be performed neat.

Alternatively, condensation of 4-aminopyridazin-3(2H)-one derivative(III), wherein R¹, R⁴ and R⁵ are as hereinbefore defined, with a boronicacid of formula (IVa), wherein R³ is as hereinbefore defined, givescompound (Ia), wherein R¹, R³, R⁴ and R⁵ are as hereinbefore defined.The reaction is carried out in the presence of a copper salt such ascupric acetate and an organic base, preferably an amine base such astriethylamine, in an inert solvent such as dioxane, methylene chlorideor tetrahydrofuran, at a temperature from −20° C. to the boiling pointof the solvent. Compounds (Ia) are equal to compounds (I) when R² ishydrogen.

Condensation of an 4-aminopyridazin-3(2H)-one derivative (Ia), whereinR¹, R³, R⁴ and R⁵ are as hereinbefore defined, with a boronic acid(IVb), wherein R² is as hereinbefore defined, gives compounds (I),wherein R¹, R², R³, R⁴ and R⁵ are as hereinbefore defined. The reactionis carried out in the presence of a copper salt such as cupric acetatein the presence of an organic base, preferably an amine base such astriethylamine, in an inert solvent such as dioxane, methylene chlorideor tetrahydrofuran, at a temperature from −20° C. to the boiling pointof the solvent.

Alternatively, compounds (I) may be obtained as shown in Scheme 2.

Oxidation of an isoxazolo[3,4-d]pyridazin-7(6H)-one of formula (II),wherein R¹, R⁴ and R⁵ are as hereinbefore defined, gives a4-nitropyridazin-3(2H)-one derivative of formula (V), wherein R¹, R⁴ andR⁵ are as hereinbefore defined. The reaction may be performed using anoxidizing agent such as cerium ammonium nitrate under acidic conditionsby methods known per se, e.g. V. Dal Piaz et al. Synthesis, 1989, 213.

Condensation of the 4-nitropyridazin-3(2H)-one derivative of formula(V), wherein R¹, R⁴ and R⁵ are as hereinbefore defined, with thecorresponding amine (VI), wherein R² and R³ are as hereinbefore defined,following methods known per se, e.g. G. Ciciani et al. Farmaco 1991, 46,873, gives compound (I), wherein R¹, R², R³, R⁴ and R⁵ are ashereinbefore defined.

According to one aspect of the present invention some specific compoundsof formula (I) and in particular those of formula (XXIV) may also beobtained as shown in Scheme 3.

Condensation of compounds (VII), in which R⁷ is an alkyl group, with anortho-substituted aryl or heteroarylamine of formula (VIII), whereineach G₁, G₂, G₃ and G₄ independently represent a nitrogen or carbon atomand —YH represents an amino, a mercapto or a hydroxy substituent, in thepresence of a dehydrating agent such as trimethylaluminium, givespyridazin-3(2H)-ones of formula (I) wherein R¹, R⁴ and R⁵ are ashereinbefore defined and Y represents a sulphur atom, an oxygen atom ora —NH— group. The reaction is preferably carried out in a solvent suchas toluene at a temperature between −78 degrees and room temperature.

Isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula (II) may be obtained asshown in Scheme 4.

Isoxazole derivatives of formula (IX), where R⁴ and R⁵ are ashereinbefore defined and R⁸ is an alkyl group, are condensed with ahydrazine of formula (X), where R¹ is as hereinbefore defined, bymethods known per se, e.g. G. Renzi et al., Gazz. Chim. Ital. 1965, 95,1478, to give isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula (II)wherein R¹, R⁴ and R⁵ are as hereinbefore defined.

Alternatively, isoxazole derivatives of formula (IX), where R⁴ and R⁵are as hereinbefore defined and R⁸ is an alkyl group, are condensed withhydrazine, by methods known per se, e.g. G. Renzi et al., Gazz. Chim.Ital. 1965, 95, 1478, to give isoxazolo[3,4-d]pyridazin-7(6H)-ones offormula (XI) wherein R⁴ and R⁵ are as hereinbefore defined. Subsequentreaction with an alkylating agent of formula (XII), wherein R¹ is ashereinbefore defined and X is a leaving group such as a chlorine or abromine atom or a methanesulfonate, p-toluenesulfonate or abenzenesulfonate group by methods known per se, e.g. V. Dal Piaz et al.Drug Des. Discovery 1996, 14, 53; or condensation with an alcohol offormula (XII) wherein R¹ is as hereinbefore described and X is a hydroxygroup in the presence of triphenylphosphine and diethylazodicarboxylateby methods known per se, e. G. O. Mitsunobu et al. J. Am. Chem. Soc.1972, 94, 679; gives isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula(II) wherein R¹, R⁴ and R⁵ are as hereinbefore defined.

Isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula (II) may also beobtained as shown in Scheme 5.

Isoxazole derivatives of formula (XIII), wherein R⁴ is hereinbeforedefined and R⁷ and R⁸ are an alkyl group, are condensed with hydrazine,by methods known per se, e.g. G. Renzi et. al., Gazz Chim. Ital. 1965,95, 1478, to give isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula (XIV)wherein R⁴ is as hereinbefore defined and R⁷ is an alkyl group.Subsequent reaction with an alkylating agent of formula (XII), whereinR¹ is as hereinbefore defined and X is a leaving group such as achlorine or a bromine atom or a methanesulfonate, p-toluenesulfonate ora benzenesulfonate group, by methods known per se, e.g. V. Dal Piaz etal. Drug Des. Discovery 1996, 14, 53; or condensation with an alcohol offormula (XII) wherein R¹ is as hereinbefore described and X is a hydroxygroup in the presence of triphenylphosphine and diethylazodicarboxylateby methods known per se, e.g. O. Mitsunobu et al. J. Am. Chem. Soc.1972, 94, 679; gives isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula(XV), wherein R¹ and R⁴ are as hereinbefore defined and R⁷ is an alkylgroup. Compounds (XV) are treated with sodium or potassium hydroxide andfurther neutralization with an inorganic acid such as hydrochloric orsulfuric acid provides the corresponding carboxylic acid derivative offormula (XVI), wherein R¹ and R⁴ are as hereinbefore defined. Thereaction is preferably carried out in a solvent such as methanol,ethanol, tetrahydrofuran or an aqueous mixture of one of the abovementioned solvents at its boiling point. Condensation of compounds (XVI)with an ortho-substituted aryl or heteroarylamine of formula (VIII),wherein each G₁, G₂, G₃ and G₄ independently represent a nitrogen orcarbon atom and Y represents an amino, a mercapto or a hydroxysubstituent, in the presence of a dehydrating agent such aspolyphosphoric acid or trimethylsilylpolyphosphate givesisoxazolo[3,4-d]pyridazin-7(6H)-ones of formula (II) wherein R¹, R⁴ andR⁵ are as hereinbefore defined. The reaction is preferably carried outin a highly boiling point solvent such as 1,2-dichlorobenzene at itsboiling point.

Pyridazin-3(2H)-ones of formula (VII) may be obtained as shown in Scheme6

An isoxazolo[3,4-d]pyridazin-7(6H)-one of formula (XV), wherein R¹ andR⁴ are as hereinbefore defined and R⁷ is an alkyl group, is hydrogenatedto yield an 4-aminopyridazin-3(2H)-one derivative (XVII), wherein R¹ andR⁴ are as hereinbefore defined and R⁷ is an alkyl group. Thehydrogenation may be performed using for example hydrogen in thepresence of a catalyst by methods known per se, e.g. V. Dal Piaz et al.Heterocycles, 1991, 32, 1173. Alternatively, the reaction may beaccomplished by transfer hydrogenation using an organic hydrogen donorand a transfer agent, such as ammonium formate or hydrazine by methodsknown per se, e. g. V. Dal Piaz et al. Heterocycles, 1991, 32, 1173.Condensation of an 4-aminopyridazin-3(2H)-one derivative (XVII), whereinR¹, R³ and R⁴ are as hereinbefore defined and R⁷ is an alkyl group withan aryl or heteroaryl bromide of formula (A) wherein R³ is ashereinbefore defined, gives compounds (VIIa), wherein R¹, R³, R⁴ and R⁵are as hereinbefore defined. The reaction is carried out in the presenceof a copper salt such as cuprous iodide and an inorganic base such aspotassium phosphate, potassium carbonate or sodium carbonate and canalso be performed in the presence of an organic base, preferably adiamine base such as N,N′-dimethylethylenediamine in an inert solventsuch as toluene, dioxane or dimethylformamide, at a temperature from−20° C. to the boiling point of the solvent or without solvent.Alternatively, condensation of an 4-aminopyridazin-3(2H)-one derivative(XVII), wherein R¹, R³ and R⁴ are as hereinbefore defined and R⁷ is analkyl group, with a boronic acid (IVa), wherein, R³ is as hereinbeforedefined, gives compounds (VIIa), wherein R¹, R³ and R⁴ are ashereinbefore defined and R⁷ is an alkyl group. The reaction is carriedout in the presence of a copper salt such as cupric acetate in thepresence of an organic base, preferably an amine base such astriethylamine, in an inert solvent such as dioxane, methylene chlorideor tetrahydrofuran, at a temperature from −20° C. to the boiling pointof the solvent. Compounds (VIIa) are equal to compounds (VII) when R² ishydrogen. Condensation of an 4-aminopyridazin-3(2H)-one derivative(VIIa), wherein R¹, R³ and R⁴ are as hereinbefore defined and R⁷ is analkyl group, with a boronic acid (IVb), wherein R² is as hereinbeforedefined, gives compounds (VII), wherein R¹, R², R³ and R⁴ are ashereinbefore defined and R⁷ is an alkyl group. The reaction is carriedout in the presence of a copper salt such as cupric acetate in thepresence of an organic base, preferably an amine base such astriethylamine, in an inert solvent such as dioxane, methylene chlorideor tetrahydrofuran, at a temperature from −20° C. to the boiling pointof the solvent.

Isoxazole derivatives of formula (IX) and (XIII) may be obtained asshown in Scheme 7.

Reaction of a 1,3-dicarbonylic compound of general formula (XX), whereinR⁴ and R⁵ are as hereinbefore defined, and a2-chloro-2-(hydroxyimino)acetate derivative of formula (XXI), wherein R⁸is as hereinbefore defined, following methods known per se, e. g. G.Renzi et al., Gazz. Chim. Ital. 1965, 95, 1478, gives isoxazolederivatives of formula (IX), wherein R⁴ and R⁵ are as hereinbeforedefined and R⁸ is an alkyl group.

Reaction of a 2,4-dioxoester derivative of general formula (XXII),wherein R⁴ is as herein before defined and R⁷ is an alkyl group, and a 2chloro-2-(hydroxyimino)acetate derivative of formula (XXI), wherein R⁸is as hereinbefore defined, following methods known per se, e. g. G.Renzi et al., Gazz. Chim. Ital. 1965, 95, 1478, gives isoxazolederivatives of formula (XIII), wherein R⁴ is as hereinbefore defined andR⁷ and R⁸ are an alkyl group.

Scheme 8

According to one aspect of the present invention some specific compoundsof formula (I) and in particular those of formula (Ic) may also beobtained as shown in Scheme 8.

Reaction of a pyridizinone of formula (Ib) wherein R¹, R², R³ and R⁵ areas hereinbefore defined and R⁴ is the rest —CHR⁹R¹⁰ wherein are R⁹ andR¹⁰ alkyl or aryl groups with an hypervalent iodine compound by methodsknown per se (Moriarty, R. M; Hu, H; Gupta S. C., Tetrahedron Lett,1981, 22, 1283-86) gives the α-hydroxylated derivative (Ic) wherein R¹,R², R³ and R⁵ are as hereinbefore defined.

Scheme 9

4-Aminopyridazin-3(2H)-ones of formula (III) may also be obtained asshown in Scheme 9.

Condensation of an isoxazolo[3,4-d]pyridazin-7(6H)-one of formula (IIb)wherein R¹ and R⁵ are as defined above with an aldehyde or a ketone offormula R⁹COR¹⁰, by methods known per se, eg. G. Ciciani et al. IIFarmaco 1991, 46, 873 leads to a substituted vinyl derivative of formula(IIc) which is then reduced using for example hydrogen in the presenceof a catalyst such as palladium on charcoal in a solvent such asmethanol, ethanol or ethyl acetate to yield the corresponding4-aminopyridazin-3(2H)-one (III).

When the defined groups R¹ to R⁵ are susceptible to chemical reactionunder the conditions of the hereinbefore described processes or areincompatible with said processes, conventional protecting groups may beused in accordance with standard practice, for example see T. W. Greeneand P. G. M. Wuts in ‘Protective Groups in Organic Chemistry’, 3^(rd)Edition, John Wiley & Sons (1999). It may be that deprotection will formthe last step in the synthesis of compounds of formula (I).

In still another aspect the present invention encompasses intermediatecompounds of formula (XVII), (VIIa) and (VII) useful in the synthesis ofcompounds of formula (I).

The compounds of formulae (IVa), (IVb), (VI), (X), (XII), (VIII), (XX),and (XXII) are known compounds or can be prepared by analogy with knownmethods.

Pharmacological Activity

PDE4 Assay Procedure

Compounds to be tested were resuspended in DMSO at a stock concentrationof 1 mM. The compounds were tested at different concentrations varyingfrom 10 μM to 10 pM to calculate an IC₅₀. These dilutions were done in96-well plates. In some cases, plates containing diluted compounds werefrozen before being assayed. In these cases, the plates were thawed atroom temperature and stirred for 15 minutes.

Ten microliters of the diluted compounds were poured into a “lowbinding” assay plate. Eighty microliters of reaction mixture containing50 mM Tris pH 7.5, 8.3 mM MgCl₂, 1.7 mM EGTA, and 15 nM [3H]-cAMP wereadded to each well. The reaction was initiated by adding ten microlitersof a solution containing PDE4. The plate was then incubated understirring for 1 hour at room temperature. After incubation the reactionwas stopped with 50 microlitres of SPA beads, and the reaction wasallowed to incubate for another 20 minutes at room temperature beforemeasuring radioactivity using standard instrumentation.

The reaction mixture was prepared by adding 90 ml of H₂O to 10 ml of 10×assay buffer (500 mM Tris pH 7.5, 8.3 mM MgCl₂, 17 mM EGTA), and 40microlitres 1 μCi/μL [3H]-cAMP. SPA beads solution was prepared byadding 500 mg to 28 ml H₂O for a final concentration of 20 mg/ml beadsand 18 mM zinc sulphate.

The results are shown in Table 1.

Example IC₅₀ PDE4 (nM) 1 2.3 4 6.8 31 4.5 32 0.59 33 0.11 36 6.4 41 1651 29 52 5.2 63 24 67 10 69 2 82 0.3 84 2.6 91 9.4 92 11 93 8.3 96 5.1

It can be seen from Table 1 that the compounds of formula (I) are potentinhibitors of phosphodiesterase 4 (PDE 4). Preferred pyridazin-3(2H)-onederivatives of the invention possess an IC₅₀ value for the inhibition ofPDE4 (determined as defined above) of less than 100 nM, preferably lessthan 50 nM and most preferably less than 30 nM. The compounds are alsocapable of blocking the production of some pro-inflammatory cytokinessuch as, for example, TNFα.

Thus, they can be used in the treatment of allergic, inflammatory andimmunological diseases, as well as those diseases or conditions wherethe blockade of pro-inflammatory cytokines or the selective inhibitionof PDE 4 could be of benefit. These disease states include asthma,chronic obstructive pulmonary disease, allergic rhinitis, rheumatoidarthritis, osteoarthritis, osteoporosis, bone-formation disorders,glomerulonephritis, multiple sclerosis; ankylosing spondylitis, Gravesophtalmopathy, myasthenia gravis, diabetes insipidus, graft rejection,gastrointestinal disorders such as irritable bowel disease, ulcerativecolitis, or Crohn disease, septic shock, adult distress respiratorysyndrome, and skin diseases such as atopic dermatitis, contactdermatitis, acute dermatomyositis and psoriasis. They can also be usedas improvers of cerebrovascular function as well as in the treatment ofother CNS related diseases such as dementia, Alzheimer's disease,depression, and as nootropic agents.

The compounds of the present invention are also of benefit whenadministered in combination with other drugs such as steroids andimmunosuppressive agents, such as cyclosporin A, rapamycin or T-cellreceptor blockers. In this case the administration of the compoundsallows a reduction Of the dosage of the other drugs, thus preventing theappearance of the undesired side effects associated with both steroidsand immunosuppressants.

Like other PDE4 inhibitors (see references above) the compounds of theinvention can also be used for blocking, after preventive and/orcurative treatment, the erosive and ulcerogenic effects induced by avariety of etiological agents, such as antiinflammatory drugs (steroidalor non-steroidal antiinflammatory agents), stress, ammonia, ethanol andconcentrated acids.

They can be used alone or in combination with antacids and/orantisecretory drugs in the preventive and/or curative treatment ofgastrointestinal pathologies like drug-induced ulcers, peptic ulcers, H.Pylori-related ulcers, esophagitis and gastro-esophageal reflux disease.

They can also be used in the treatment of pathological situations wheredamage to the cells or tissues is produced through conditions likeanoxia or the production of an excess of free radicals. Examples of suchbeneficial effects are the protection of cardiac tissue after coronaryartery occlusion or the prolongation of cell and tissue viability whenthe compounds of the invention are added to preserving solutionsintended for storage of transplant organs or fluids such as blood orsperm. They are also of benefit on tissue repair and wound healing.

Accordingly, the pyridazin-3(2H)-one derivatives of the invention andpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising such compound and/or salts thereof, may be usedin a method of treatment of disorders of the human body which comprisesadministering to a patient requiring such treatment an effective amountof a pyridazin-3(2H)-one derivative of the invention or apharmaceutically acceptable salt thereof.

The results of table I show that the compounds of formula (I) are potentinhibitors of phosphodiesterase 4 (PDE4) and are therefore useful in thetreatment or prevention of pathological conditions, diseases anddisorders known to be susceptible of amelioration by inhibition of PDE4,such as asthma, chronic obstructive pulmonary disease, rheumatoidarthritis, atopic dermatitis, psoriasis or irritable bowel disease.

The compounds of the present invention can also be used in combinationwith other drugs known to be effective in the treatment of thesediseases. For example, in combination with steroids, immunosuppressiveagents, T-cell receptor blockers and/or antiinflammatory drugs forsimultaneous, separate or sequential use in the treatment of the humanor animal body

Accordingly, another embodiment of he invention is the use of thecompounds of formula (I) in the manufacture of a medicament fortreatment or prevention of pathological conditions, diseases anddisorders known to be susceptible of amelioration by inhibition of PDE4,as well as a method for treating a subject afflicted with a pathologicalcondition or disease susceptible to amelioration by inhibition of PDE4,which comprises administering to said subject an effective amount of acompound of formula (I).

The present invention also provides pharmaceutical compositions whichcomprise, as an active ingredient, at least a pyridazin-3(2H)-onederivative of formula (I) or a pharmaceutically acceptable salt thereofin association with at least one pharmaceutically acceptable excipientsuch as a carrier or diluent. The active ingredient may comprise 0.001%to 99% by weight, preferably 0.01% to 90% by weight, of the compositiondepending upon the nature of the formulation and whether furtherdilution is to be made prior to application. Preferably the compositionsare made up in a form suitable for oral, topical, nasal, rectal,percutaneous or injectable administration.

The pharmaceutically acceptable excipients which are admixed with theactive compound, or salts of such compound, to form the compositions ofthis invention are well-known per se and the actual excipients useddepend inter alia on the intended method of administering thecompositions.

Compositions for oral administration may take the form of tablets,retard tablets, sublingual tablets, capsules, inhalation aerosols,inhalation solutions, dry powder inhalation, or liquid preparations,such as mixtures, elixirs, syrups or suspensions, all containing thecompound of the invention; such preparations may be made by methodswell-known in the art.

The diluents which may be used in the preparation of the compositionsinclude those liquid and solid diluents which are compatible with theactive ingredient, together with colouring or flavouring agents, ifdesired. Tablets or capsules may conveniently contain between 2 and 500mg of active ingredient or the equivalent amount of a salt thereof.

The liquid composition adapted for oral use may be in the form ofsolutions or suspensions. The solutions may be aqueous solutions of asoluble salt or other derivative of the active compound in associationwith, for example, sucrose to form a syrup. The suspensions may comprisean insoluble active compound of the invention or a pharmaceuticallyacceptable salt thereof in association with water, together with asuspending agent or flavouring agent.

Compositions for parenteral injection may be prepared from solublesalts, which may or may not be freeze-dried and which may be dissolvedin pyrogen free aqueous media or other appropriate parenteral injectionfluid.

Compositions for topical administration may take the form of ointments,creams or lotions, all containing the compound of the invention; suchpreparations may be made by methods well-known in the art.

Effective doses are normally in the range of 10-600 mg of activeingredient per day. Daily dosage may be administered in one or moretreatments, preferably from 1 to 4 treatments, per day.

The present invention will be further illustrated by the followingexamples. The examples are given by way of illustration only and are notto be construed as a limiting.

The syntheses of the compounds of the invention and of the intermediatesfor use therein are illustrated by the following Examples (includingPreparation Examples (Preparations 1 to 99)) which do not limit thescope of the invention in way.

¹H Nuclear Magnetic Resonance Spectra were recorded on a Varian Gemini300 spectrometer.

Low Resolution Mass Spectra (m/z) were recorded on a Micromass ZMD massspectrometer using ESI ionization.

Melting points were recorded using a Perkin Elmer DSC-7 apparatus.

The chromatographic separations were obtained using a Waters 2695 or2795 system equipped with a Symmetry C18 (2.1×10 mm, 3.5 mM) columnusing one of the following methods:

Method A). The mobile phase was formic acid (0.4 mL), ammonia (0.1 mL),methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.46mL), ammonia (0.115 mL) and water (1000 mL) (A): initially from 0% to95% of B in 10.5 min at a flow rate of 0.4 ml/min, from 10.5 to 11.0 minthe flow rate was lineary increased to 0.8 ml/min and maintained inthese conditions until minute 12.0. Reequilibration time between twoinjections was 2 min. The injection volume was 5 microliter. Diode arraychromatograms were collected at 210 nM.

Method B) The mobile phase was formic acid (0.4 mL), ammonia (0.1 mL),methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.46mL), ammonia (0.115 mL) and water (1000 mL) (A): initially from 0% to95% of B in 20 min, and then 4 min. with 95% of B. The reequilibrationtime between two injections was 5 min. The flow rate was 0.4 mL/min. Theinjection volume was 5 microliter. Diode array chromatograms werecollected at 210 nM.

PREPARATION EXAMPLES Preparation 1 (Scheme 7) Ethyl5-methyl-4-(pyridin-3-ylcarbonyl)isoxazole-3-carboxylate

To an ice-cooled solution of sodium ethoxide (5.9 g, 110 mmol) inabsolute ethanol (150 mL) 1-pyridin-3-yl-butane-1,3-dione (Ohta, S. etal., Chem. Pharm. Bull., 1981, 29, 2762) (16.4 g, 100 mmol) was addedportionwise and the mixture was stirred at 0° for 30 min. A solution ofethyl chloro(hydroximino)acetate (16.7 g, 110 mmol) in absolute ethanol(50 mL) was added dropwise and the final mixture was stirred at roomtemperature overnight. The mixture was concentrated and the residue thusobtained was suspended in ethyl acetate, washed with saturated —NH4Clsolution, water and brine, dried and concentrated to yield the titlecompound: (25.7 g, 98% yield) as a yellow solid.

δ(CDCl₃): 1.15 (t, 3H), 2.58 (s, 3H), 4.18 (q, 2H), 7.42 (m, 1H), 8.10(m, 1H), 8.81 (m, 1H), 8.95 (m, 1H).

Preparation 2 (Scheme 7) Ethyl5-methyl-4-(pyridin-2-ylcarbonyl)isoxazole-3-carboxylate

Obtained as a yellow solid (99%) from 1-pyridin-2-yl-butane-1,3-dione(Chiswell et al., Inorg. Chim. Acta 1972, 6, 629) and ethylchloro(hydroximino)acetate following the experimental proceduredescribed in Preparation 1.

LRMS: m/Z 261 (M+1)⁺.

Preparation 3 (Scheme 4)3-Methyl-4-pyridin-3-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Hydrazine monohydrate (6.0 g, 120 mmol) was added dropwise to a solutionof the title compound of Preparation 1 (26.0 g, 100 mmol) in dry-ethanol(500 mL) and the resulting mixture was stirred overnight. After coolingwith an ice bath, a precipitate was formed which was collected byfiltration and washed with diethyl ether to yield the title compound(17.2 g, 76% yield) as a yellow solid.

δ(DMSO-d6): 2.57 (s, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 8.72 (d, 1H), 8.80(s,1H).

Preparation 4 (Scheme 4)3-Methyl-4-pyridin-2-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained as a yellow solid (60%) from the title compound of Preparation2 using the experimental procedure described in Preparation 3.

δ(DMSO-d6): 2.92 (s, 3H), 7.58 (m, 1H), 7.98 (m, 2H), 8.77 (m, 1H).

Preparation 5 (Scheme 4)6-Ethyl-3-methyl-4-pyridin-3-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

To a suspension of the title compound of Preparation 3 (17.2 g, 75.6mmol) and anhydrous potassium carbonate (62 g, 453 mmol) in drydimethylformamide (100 mL) was added ethyl bromide (57.0 g, 525 mmol)and the resulting mixture stirred at r.t. overnight. The mixture wasconcentrated and the residue thus obtained was suspended indichloromethane, washed with water and brine, dried and concentrated toyield the title compound (8.44 g, 44% yield) as a yellow solid.

δ(CDCl₃): 1.42 (t, 3H), 2.58 (s, 3H), 4.23 (q, 2H), 7.55 (m,1H), 7.92(m,1H), 8.80 (m, 2H).

Preparation 6 (Scheme 4)6-Ethyl-3-methyl-4-pyridin-2-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (27%) from the title compound from Preparation 4 following theexperimental procedure described in Preparation 5.

δ(CDCl₃): 1.41 (t, 3H), 2.98 (s, 3H), 4.33 (q, 2H), 7.42 (m,1H), 7.92(m,1H), 8.05 (m, 1H), 8.68 (m, 1H).

Preparation 7 (Scheme 4)6-Ethyl-3-methyl-4-pyridin-4-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (82%) from3-methyl-4-pyridin-4-yl-6H-isoxazolo[3,4-d]pyridazin-7-one (V. Dal Piazet al., J. Pharmac. Sci., 1991, 80, 341-348) following the experimentalprocedure described in Preparation 5.

δ(CDCl₃): 1.39 (t, 3H), 2.58 (s, 3H), 4.31 (q, 2H), 7.52 (d, 2H), 8.80(d, 2H).

Preparation 8 (Scheme 4)6-(Cyclopropylmethyl)-3-methyl-4-pyridin-3-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (44%) from the title compound from Preparation 3 andcyclopropylmethyl bromide following the experimental procedure describedin Preparation 5.

δ(DMSO-d₆): 0.40 (m, 4H), 1.32 (m, 1H), 2.58 (s, 3H), 4.00 (d, 2H), 7.60(m,1H), 8.10 (m,1H), 8.78 (m, 1H), 8.11 (m, 1H).

Preparation 9 (Scheme 4)6-(Cyclopropylmethyl)-3-methyl-4-pyridin-2-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (98%) from the title compound from Preparation 4 andcyclopropylmethyl bromide following the experimental procedure describedin Preparation 5.

δ(CDCl₃): 0.55 (m, 4H), 1.42 (m, 1H), 2.98 (s, 3H), 4.03 (d, 2H), 7.40(m, 1H), 7.82 (m,1H), 8.01 (m, 1H), 8.72 (m, 1H).

Preparation 10 (Scheme 4)6-(Cyclopropylmethyl)-3-methyl-4-pyridin-4-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (85%) from3-methyl-4-pyridin-4-yl-6H-isoxazolo[3,4-d]pyridazin-7-one (V. Dal Piazet al., J. Pharmac. Sci., 1991, 80, 341-348) and cyclopropylmethylbromide following the experimental procedure described in Preparation 5.

δ(DMSO-d₆): 0.54 (m, 4H), 1.35 (m, 1H), 2.58 (s, 3H), 4.01 (d, 2H), 7.65(d, 2H), 8.78 (d, 2H).

Preparation 11 (Scheme 4) 6-(2-Hydroxyethyl)-3-methyl4-pyridin-3-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (66%) from the title compound from Preparation 3 and2-bromoethanol following the experimental procedure described inPreparation 5.

δ(DMSO-d₆): 2.60 (s, 3H), 4.05 (m, 2H), 4.41 (t, 3H), 7.52 (m,1H), 7.95(m, 1H), 8.10 (m,1H), 8.60 (m, 2H).

Preparation 12 (Scheme 4)6-(2-Hydroxyethyl)-3-methyl-4-pyridin-2-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (92%) from the title compound from Preparation 4 and2-bromoethanol following the experimental procedure described inPreparation 5.

δ(CDCl₃): 2.41 (m, 1H), 2.97 (s, 3H), 4.13 (m, 2H), 4.43 (m, 2H), 7.42(m, 1H), 7.85 (m,1H), 8.00 (m, 1H), 8.70 (m, 1H).

Preparation 13 (Scheme 4)6-(2-Hydroxyethyl)-3-methyl-4-pyridin-4-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (70%) from3-methyl-4-pyridin-4-yl-6H-isoxazolo[3,4-d]pyridazin-7-one (V. Dal Piazet al., J. Pharmac. Sci., 1991, 80, 341-348) and 2-bromoethanolfollowing the experimental procedure described in Preparation 5.

δ(DMSO-d₆): 2.60 (s, 3H), 3.78 (q, 2H), 4.18 (t, 2H), 4.83 (t, 1H), 7.68(d, 2H), 8.78 (d, 2H).

Preparation 14 (Scheme 1)5-Acetyl-4-amino-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one

A mixture of the title compound of Preparation 5 (8.44 g, 33 mmol) and10% palladium on charcoal (1.7 g) in ethanol (400 mL) was shaken underhydrogen at room temperature and 2 bar for 6 h. The catalyst wasfiltered off and the solvent was removed under reduced pressure to yieldthe title compound (6.43 g, 76% yield).

δ(CDCl₃): 1.42 (t, 3H), 1.82 (s, 3H), 4.25 (q, 2H), 7.45 (m,1H), 7.80(m,1H), 8.70 (m, 2H).

Preparation 15 (Scheme 1)5-Acetyl-4-amino-2-ethyl-6-pyridin-2-pyridazin-3(2H)-one

Obtained after column chromatography purification (40%) from the titleproduct of Preparation 6 following the procedure described inPreparation 14.

δ(CDCl₃): 1.41 (t, 3H), 1.80 (s, 3H), 4.30 (q, 2H), 7.05 (bs, 2H),7.38(m, 1H), 7.82 (m, 2H), 8.62 (m, 1H).

Preparation 16 (Scheme 1)5-Acetyl-4-amino-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained (92%) from the title product of Preparation 7 following theprocedure described in Preparation 14.

δ(CDCl₃): 1.37 (t, 3H), 1.82 (s, 3H), 4.24 (q, 2H), 7.44 (d, 2H), 8.70(d, 2H).

Preparation 17 (Scheme 1)5-Acetyl-4-amino-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one

A mixture of the title compound of Preparation 9 (1.0 g, 3.50 mmol), 10%palladium on charcoal (56 mg) and ammonium formate (3.97 g, 63 mmol) inmethanol (30 mL) was refluxed for 2 hours. Then the catalyst wasfiltered off and the solvent was removed under reduced pressure. Theresulting residue was partitioned between dichloromethane and water andthe organic layer was washed with water twice. It was dried and solventremoved under reduced pressure to yield the title compound (471 mg,47%).

δ(CDCl₃): 0.45 (m, 4H), 1.37 (m, 1H), 1.81 (s, 3H), 4.02 (d, 2H), 7.40(m,1H), 7.80 (m,1H), 8.72 (m, 2H).

Preparation 18 (Scheme 1)5-Acetyl-4-amino-2-(cyclopropylmethyl)-6-pyridin-2-ylpyridazin-3(2H)-one

Obtained (90%) from the title product of Preparation 9 following theprocedure described in Preparation 17.

δ(CDCl₃): 0.45 (m, 4H), 1.38 (m, 1H), 1.80 (s, 3H), 4.03 (d, 2H), 7.01(bs, 2H), 7.52 (m, 1H), 7.83 (m,2H), 8.62; (m, 1H).

Preparation 19 (Scheme 1)5-Acetyl-4-amino-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained (96%) from the title product of Preparation 10 following theprocedure described in Preparation 14.

δ(DMSO-d₆): 0.41 (m, 4H), 1.28 (m, 1H), 1.82 (s, 3H), 3.97 (d, 2H), 7.42(d, 2H), 7.82 (bs, 2H), 8.65 (d, 2H).

Preparation 20 (Scheme 1)5-Acetyl-4-amino-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one

Obtained (50%) from the title product of Preparation 11 following theprocedure described in Preparation 17. It was refluxed for 2 hours andthen stirred at room temperature overnight.

δ(CDCl₃): 1.78 (s, 3H), 4.22 (m, 2H), 4.41 (m, 3H), 7.45 (m,1H), 7.80(m, 1H), 8.78 (m,2H).

Preparation 21 (Scheme 1)5-Acetyl-4-amino-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one

Obtained (64%) from the title product of Preparation 12 following theprocedure described in Preparation 17.

δ(CDCl₃): 1.78 (s, 3H), 4.13 (t, 2H), 4.40 (t, 2H), 7.10 (bs, 2H), 7.38(m, 1H), 7.82 (m, 2H), 8.62 (m, 1H).

Preparation 22 (Scheme 1)5-Acetyl-4-amino-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained (55%) from the title product of Preparation 13 following theprocedure described in Preparation 14.

δ(DMSO-d₆): 1.82 (s, 3H), 3.75 (m, 2H), 4.18 (t, 2H), 4.81 (bs, 1H),7.48 (d, 2H), 7.85 (bs, 1H), 8.63 (d, 2H).

Preparation 23 (Scheme 7) Ethyl5-methyl-4-thiene-2-carbonyl)isoxazole-3-carboxylate

Obtained as a solid (50%) from 1-thiophen-2-yl-butane-1,3-dione (Gash,V. W.; Can J. Chem., 1967, 45, 2109-12) and ethylchloro(hydroximino)acetate following the experimental proceduredescribed in Preparation 1.

δ(CDCl₃): 1.15 (t, 3H), 2.55 (s, 3H), 4.20 (q, 2H), 7.20-7.70 (m, 3H).

Preparation 24 (Scheme 4)3-Methyl-4-thien-2-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained as a solid (57%) from the title compound of Preparation 23using the experimental procedure described in Preparation 3.

δ(CDCl₃): 2.78 (s, 3H), 7.18-7.59 (m, 3H), 9.62 (s, 1H).

Preparation 25 (Scheme 4)6-Ethyl-3-methyl-4-thien-2-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (83%) from the title compound from Preparation 24 following theexperimental procedure described in Preparation 5.

δ(CDCl₃): 1.41 (t, 3H), 2.78 (s, 3H), 4.28 (q, 2H), 7.18-7.59 (m, 3H).

Preparation 26 (Scheme 1)5-Acetyl-4-amino-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one

Obtained (50%) from the title product of Preparation 25 following theprocedure described in Preparation 14.

δ(CDCl₃): 1.41 (t, 3H), 1.98 (s, 3H), 4.22 (q, 2H), 7.10-7.41 (m, 3H).

Preparation 27 (Scheme 7) Ethyl4-(4-fluorobenzoyl)-5-methylisoxazole-3-carboxylate

Obtained (95%) from 1-(4-fluorophenyl)butane-1,3-dione (Joshi, K. C.;Pathak, V. N.; Garg, U. J. Indian Chem. Soc. 1983, 60, 1074-1076) andethyl chloro(hydroximino)acetate following the experimental proceduredescribed in Preparation 1.

δ(CDCl₃): 1.1 (t, 3H), 2.50 (s, 3H), 4.20 (q, 2H), 7.20 (m, 2H), 7.80(m, 2H).

Preparation 28 (Scheme 4)4-(4-Fluorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (87%) from the title compound of Preparation 27, using theexperimental procedure described in Preparation 3.

δ(CDCl₃): 2.55 (s, 3H), 7.30 (m, 2H), 7.60 (m, 2H).

Preparation 29 (Scheme 4)6-Ethyl-4-(4-fluorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

To a suspension of the title compound of Preparation 28 (0.49 g, 2.0mmol) and anhydrous potassium carbonate (0.55 g, 4.0 mmol) in drydimethylformamide (5.3 mL) was added ethyl bromide (0.44 g, 4.03 mmol)and the resulting mixture heated at 110° C. for 40 minutes. Thenice-water was added (30 mL) and the resulting precipitate collected byfiltration to afford the title compound (0.47 g, 86%) as a yellow solid.

δ(CDCl₃): 1.40 (t, 3H), 2.58 (s, 3H), 4.23 (q, 2H), 7.20 (m,2H), 7.58(m,2H).

Preparation 30 (Scheme 2)5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-nitropyridazin-3(2H)-one

To a stirred suspension of the title compound of Preparation 29 (0.5 g,1.83 mmol) in a mixture of acetic acid (7.3 mL), water (7.3 mL) andnitric acid (2.5 mL), cerium ammonium nitrate (6.0 g, 11 mmol) was addedportionwise during 40 min. Addition of ice-cold water gave a crudeprecipitate which was filtered and washed with cold water to yield thetitle product (45% yield).

δ(CDCl₃): 1.43 (t, 3H), 2.20 (s, 3H), 4.40 (q, 2H), 7.20 (m, 2H), 7.48(m, 2H).

Preparation 31 (Scheme 7) Ethyl4-(3-fluorobenzoyl)-5-methylisoxazole-3-carboxylate

Obtained (79%) from 1-(3-fluorophenyl)butane-1,3-dione (Joshi, K. C.;Pathak, V. N.; Garg, U. J. Indian Chem. Soc. 1983, 60, 1074-1076) andethyl chloro(hydroximino)acetate following the experimental proceduredescribed in Preparation 1.

δ(CDCl₃): 1.10 (t, 3H), 2.60 (s, 3H), 4.15 (q, 2H), 7.30 (m, 4H).

Preparation 32 (Scheme 4)4-(3-Fluorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (81%) from the title compound of Preparation 31 following theexperimental procedure described in Preparation 3.

δ(CDCl₃): 2.60 (s, 3H), 7.3 (m, 4H), 9.90 (s, 1H).

Preparation 33 (Scheme 4)6-Ethyl-4-(3-fluorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (84%) from the title compound from Preparation 32 following theexperimental procedure described in Preparation 5.

δ(CDCl₃): 1.40 (t, 3H), 2.58 (s, 3H), 4.30 (q, 2H), 7.30 (m, 3H), 7.50(m, 1H).

Preparation 34 (Scheme 4)6-(Cyclopropylmethyl)-4-(3-fluorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (37%) from the title compound from Preparation 32 andcyclopropylmethyl bromide following the experimental procedure describedin Preparation 5. The product was purified by column chromatography.

δ(CDCl₃): 0.52 (m, 4H), 1.38 (m, 1H), 2.58 (s, 3H), 4.07 (d, 2H), 7.30(m, 3H), 7.55 (m, 1H).

Preparation 35 (Scheme 4)4-(3-Fluorophenyl)-6-isopropyl-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

To a stirred solution of the title compound of preparation 32 (2.0 g,8.16 mmol) in 30 mL of dry THF, triphenylphosphine (2.16 g, 8.24 mmol)and isopropanol (0.68 mL, 8.97 mmol) were added. The mixture was cooledto 0° C. and then diethylazadicarboxylate (1.3 mL, 8.24 mmol) was addeddropwise. The final mixture was let to warm up to room temperature andthe stirred for 24 h. Finally solvent was removed and the final productwas isolated by column chromatography in a 37% yield.

δ(CDCl₃): 1.38 (d, 6H), 2.58 (s, 3H), 5.41 (h, 1H), 7.32 (m, 3H), 7.52(m, 1H).

Preparation 36 (Scheme 2)5-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-nitropyridazin-3(2H)-one

Obtained (40%) from the title product of Preparation 33 following theexperimental procedure described in Preparation 30.

δ(CDCl₃): 1.50 (t, 3H), 2.20 (s, 3H), 4.40 (q, 2H), 7.20 (m, 3H), 7.46(m, 1H).

Preparation 37 (Scheme 2)5-Acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-4-nitropyridazin-3(2H)-one

Obtained (23%) from the title product of Preparation 34 following theexperimental procedure described in Preparation 30.

δ(CDCl₃): 0.54 (m, 4H), 1.51 (m, 1H), 2.21 (s, 3H), 4.16 (d, 2H), 7.22(m, 3H), 7.45 (m, 1H).

Preparation 38 (Scheme 2)5-Acetyl-6-(3-fluorophenyl)-2-isopropyl-4-nitropyridazin-3(2H)-one

Obtained (40%) from the title product of Preparation 35 following theexperimental procedure described in Preparation 30.

δ(CDCl₃): 1.44 (d, 6H), 2.20 (s, 3H), 5.45 (h, 1H), 7.16 (m, 3H), 7.50(m, 1H).

Preparation 39 (Scheme 4)4-(3-Chlorophenyl)-6-(cyclopropylmethyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (97%) from4-(3-chlorophenyl)-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one (DalPiaz, V et al., J. Med. Chem. 1997, 40, 1417) and cyclopropylmethylbromide following the experimental procedure described in Preparation 5.The product was purified by column chromatography.

LRMS: m/z 316 (M+1)⁺.

Preparation 40 (Scheme 2)5-Acetyl-6-(3-chlorophenyl)-2-(cyclopropylmethyl)-4-nitropyridazin-3(2H)-one

Obtained (21%) from the title product of Preparation 39 following theexperimental procedure described in Preparation 30.

LRMS: m/z 348 (M+1)⁺.

Preparation 41 (Scheme 7) Ethyl4-[ethoxy(oxo)acetyl]-5-methylisoxazole-3-carboxylate

To a well stirred solution of sodium methoxide (10.5 g, 0.15 mol) in 100mL of dry ethanol, diethyl oxalate (21 mL, 0.15 mol) was added dropwiseand the mixture was warmed to 45° C. Then dry acetone (45 mL, 0.60 mol)was added and after 30 min the final mixture was refluxed for 3 hoursand stirred at room temperature overnight. Finally solvent was removedand 100 mL of fresh dry ethanol were added. The mixture was cooled to,0° C. and a solution of ethyl chloro(hydroximino)acetate (27.2 g, 0.18mol) in 25 mL of dry ethanol was added dropwise. Then it was stirred at0° C. for 30 min and at room temperature for 3 days. Finally solvent wasremoved and the crude thus obtained was partitioned between ethylacetate and water. It was dried and solvent removed to yield the desiredproduct (90%) as an orange oil.

δ(CDCl₃): 1.39 (m, 6H), 2.68 (s; 3H), 4.40 (m, 4H).

Preparation 42 (Scheme 5) Ethyl3-methyl-7-oxo-6,7-dihydroisoxazolo[3,4-d]pyridazine 4-carboxylate

Obtained as a solid (57%) from the title compound of Preparation 41using the experimental procedure described in Preparation 3.

δ(CDCl₃): 1.41 (t, 3H), 3.01 (s, 3H), 4.50 (q, 2H), 6.30 (s, 1H).

Preparation 43 (Scheme 5) Ethyl6-ethyl-3-methyl-7-oxo-6,7-dihydroisoxazolo[3,4-d]pyridazine-4-carboxylate

Obtained (90%) from the title compound of Preparation 42 following theexperimental procedure described in Preparation 5.

δ(CDCl₃): 1.42 (m, 6H), 3.00 (s, 3H), 4.25 (q, 2H), 4.48 (q, 2H)

Preparation 44 (Scheme 6) Ethyl4-acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

Obtained (98%) from the title product of Preparation 43 following theprocedure described in Preparation 14.

δ(CDCl₃): 1.38 (m, 6H), 2.30 (s, 3H), 4.22 (q, 2H), 4.42 (q, 2H), 7.50(bs, 2H).

Preparation 45 (Scheme 6) Ethyl4-acetyl-5-[(3-chlorophenyl)amino]-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

A mixture of the title compound of Preparation 44 (506 mg, 2.0 mmol),3-chlorophenylboronic acid (626 mg, 4.0 mmol), anhydrous cupric acetate(540 mg, 3.0 mmol), triethylamine (0.56 mL, 4.0 mmol) and activatedmolecular sieves (1.6 g, 4 Å) in dry dichloromethane (25 mL) was stirredunder air exposure at room temperature for 48 h. The reaction wasfiltered and the solvent removed under reduced pressure. The resultingresidue was recrystallized from ethyl acetate (202 mg, 64% yield).

δ(CDCl₃): 1.38 (t, 3H), 1.42 (t, 3H), 2.01 (s, 3H), 4.42 (m, 4H), 6.97(m, 1H), 7.16 (m, 1H), 7.35 (m, 2H), 7.05 (s, 1H).

Preparation 46 (Scheme 5)6-Ethyl-3-methyl-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazine-4-carboxylicacid

To a stirred solution of the title compound of preparation 43 (2.73 g,11 mmol) in 90 mL of a 2:1 methanol/THF mixture, a solution of lithiumhydroxide (1.87 g, 45 mmol) in 6 mL of water was added dropwise. Thefinal mixture was stirred at room temperature for 5 hours and thendiluted with some water and acidified with HCl 2N. It was extracted withethyl acetate, dried and solvent removed to yield (89%) the titleproduct.

δ(DMSO-d₃): 1.35 (t, 3H), 2.98 (s, 3H), 4.15 (q, 2H).

Preparation 47 (Scheme 5)4-(1,3-Benzoxazol-2-yl)-6-ethyl-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

To a 100° C. pre-warmed suspension of PPSE (6 g) in 10 mL of1,2-dichlorobenzene, a solution of 2-aminophenol (0.48 g, 4.4 mmol) in10 mL of 1,2-dichlorobenzene was added and the mixture was stirred for awhile. Then the title compound of preparation 46 (1.08 g, 4.84 mmol) wasadded in portions and the mixture was refluxed overnight. Then it waslet to cool down and poured onto ice-water vigorously stirring. It wasneutralized with potassium carbonate and extracted with dichloromethane.The organic layer was dried and solvent removed to yield a crude productthat was purified by column chromatography. The title product wasisolated (44%).

δ(CDCl₃): 1.42 (t, 3H), 3.25 (s, 3H), 4.38 (q, 2H), 7.41 (m, 2H), 7.70(m, 1H), 7.82 (m, 1H).

Preparation 48 (Scheme 1)5-Acetyl-4-amino-6-(1,3-benzoxazol-2-yl)-2-ethylpyridazin-3(2H)-one

Obtained (98%) from the title product of Preparation 47 following theprocedure described in Preparation 14.

Preparation 49 5-Acetyl-4-amino-2-ethyl-6-phenylpyridazin-3(2H)-one

A mixture of6-ethyl-3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (Dal Piaz,V et al, J. Med. Chem. 1997, 40, 1417) (2.0 g, 7.83 mmol) and 10%palladium on charcoal (400 mg) in ethanol (400 ml) was shaken underhydrogen at room temperature and 2 bar for 3 h. The catalyst wasfiltered off and the solvent was removed under reduced pressure to yieldthe title compound (1.97 g, 98% yield).

m.p. 150.8-152.7° C. δ(CDCl₃): 1.43 (t, 3H), 1.67 (bs, 2H), 1.78 (s,3H), 4.26 (q, 2H), 7.45 (s, 5H).

Preparation 50 5-Acetyl-4-amino-6-thiophen-2-yl-2H-pyridazin-3-one

Obtained (78%) from the title compound of Preparation 24 following theprocedure described in Preparation 17.

δ(CDCl₃): 2.00 (s, 3H), 7.07-7.50 (m, 3H).

Preparation 515-Acetyl-4-amino-2-cyclopropylmethyl-thiophen-2-yl-2H-pyridazin-3-one

Obtained (60%) from the title compound of Preparation 50 andcyclopropylmethyl bromide following the procedure described inPreparation 5.

δ(CDCl₃): 0.42-0.62 (m, 4H), 1.40 (m, 1H), 1.99 (s, 3H), 4.06 (d, 2H),7.04-7.50 (m, 3H).

Preparation 52 Ethyl5-methyl-4-(thien-3-ylcarbonyl)isoxazole-3-carboxylate

Obtained as a solid (70%) from 1-thiophen-3-yl-butane-1,3-dione (Hams,J; Levine, H; J. Am. Chem. Soc., 1948, 70, 3360) and ethylchloro(hydroximino)acetate following the experimental proceduredescribed in Preparation 1.

δ(CDCl₃): 1.17 (t, 3H), 2.58 (s, 3H), 4.20 (q, 2H), 7.36-7.70 (m, 3H).

Preparation 53 3-Methyl-4-thien-3-ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained as a solid (38%) from the title compound of Preparation 52using the experimental procedure described in Preparation 3.

δ(CDCl₃): 2.60 (s, 3H), 7.36-8.00 (m, 3H), 12.62 (s, 1H).

Preparation 54 6-Ethyl-3-methy-4-thien-3ylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (71%) from the title compound from Preparation 53 following theexperimental procedure described in Preparation 5.

δ(CDCl₃): 1.42 (t, 3H), 2.67 (s, 3H), 4.26 (q, 2H), 7.30-7.62 (m, 3H).

Preparation 55 5-Acetyl-4-amino-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one

Obtained (84%) from the title product of Preparation 54 following theprocedure described in Preparation 14.

δ(CDCl₃): 1.41 (t, 3H), 1.88 (s, 3H), 4.26 (q, 2H), 7.17-7.48 (m, 3H).

Preparation 566-Ethyl-4-phenyl-3-styryl-6H-isoxazolo[3,4-d]pyridazin-7-one

To a freshly prepared solution of sodium methoxide (108 mg, 1.96 mmol)in methanol (2 ml), a solution of6-ethyl-3-methyl-4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one (500 mg,1.96 mmol) (Dal Piaz, V.; Giovannoni, M. P.; Castellana, C.; et al, J.Med. Chem. 1997, 40, 1417-1421) in of dry methanol (2 ml) was added andthe mixture was stirred for a while. Then, benzaldehyde (0.40 ml, 3.92mmol) was added dropwise and the final mixture was refluxed for 2 hours.The resulting suspension was let to cool down and the final product (514mg, 76%-yield) was collected by filtration.

δ(CDCl₃): 1.40 (t, 3H), 4.31, (q, 2H), 6.80 (d, 1H), 7.35 (m, 5H), 7.68(m, 6H).

Preparation 576-Ethyl-4-phenyl-3-(2-thiophen-3-yl-vinyl)-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained (75%) from6-ethyl-3-methyl-4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one (500 mg,1.96 mmol) (Dal Piaz, V.; Giovannoni, M. P.; Castellana, C.; et al, J.Med. Chem. 1997, 40, 1417-1421) and thiophene-3-carbaldehyde followingthe procedure described in Preparation 56.

δ(CDCl₃): 1.42 (t, 3H), 4.30 (q, 2H), 6.58 (d, 1H), 6.98 (d, 1H), 7.28(m, 1H), 7.42 (m, 1H), 7.63 (m, 6H).

Preparation 584-Amino-2-ethyl-6-phenyl-5-(3-phenylpropionyl)pyridazin-3(2H)-one

A mixture of the title compound of preparation 56 (514 mg, 1.50 mmol)and 10% palladium on charcoal (100 mg) in ethanol (100 ml) was shakenunder hydrogen at room temperature and 2 bar overnight. The catalyst wasfiltered off and the solvent was removed under reduced pressure to yieldthe title compound (487 mg, 95% yield).

m.p. 115.1-116.1° C. δ(CDCl₃): 1.40 (t, 3H), 2.28 (t, 2H), 2.68 (t, 2H),4.25 (q, 2H), 6.78 (m, 2H), 7.05 (m, 3H), 7.45 (m, 5H).

Preparation 594-Amino-2-ethyl-6-phenyl-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one

Obtained (67%) from the title compound of Preparation 57 following theprocedure described in Preparation 58.

δ(CDCl₃): 1.41 (t, 3H), 2.30 (t, 2H), 2.70 (t, 2H), 4.25 (q, 2H), 6.08(d, 1H), 6.54-6.62 (m, 2H), 7.08-7.58 (m, 7H).

Preparation 60 4-(Benzofuran-2-carbonyl)-5-methyl-isoxazole 3-carboxylicacid ethyl ester

Obtained as a solid (80%) from: 1-benzofuran-2-yl-butane-1,3-dione(Richard, F.; Carreyre, H.; Coustard, J. M.; Bachman, C.; Perot, G.,Tetrahedron 1998, 54(49), 14757-14766) and ethylchloro(hydroximino)acetate following the experimental proceduredescribed in Preparation 1.

δ(CDCl₃): 1.10 (t, 3H), 2.21 (s, 3H), 4.15 (q, 2H), 7.16-7.80 (m, 5H).

Preparation 614-Benzofuran-2-yl-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (65%) from the title compound of Preparation 60using the experimental procedure described in Preparation 3.

δ(CDCl₃): 2.99 (s, 3H), 7.29-7.49 (m, 3H), 7.70-7080 (m, 2H).

Preparation 624-Benzofuran-2-yl-6-ethyl-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained (67%) from the title compound from Preparation 61 following theexperimental procedure described in Preparation 5.

δ(CDCl₃): 1.44 (t, 3H), 3.07 (s, 3H), 4.32 (q, 2H), 7.27-7.76 (m, 5H).

Preparation 635-Acetyl-4-amino-6-benzofuran-2-yl-2-ethyl-2H-pyridazin-3-one

Obtained (90%) from the title product of Preparation 62 following theprocedure described in Preparation 17.

δ(CDCl₃): 1.44 (t, 3H), 1.99 (s, 3H), 4.27 (q, 2H), 7.16 (s, 1H),7.27-7.72 (m, 6H).

Preparation 646-(Cyclopropylmethyl)-4-(4-fluorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one

Obtained (46%) from the title compound from Preparation 28 andcyclopropylmethyl bromide following the experimental procedure describedin Preparation 5. The product was purified by column chromatography.

δ(CDCl₃): 0.54 (m, 4H), 1.38 (m, 1H), 2.58 (s, 3H), 4.08 (d, 2H), 7.28(d, 2H), 7.57 (dd, 2H).

Preparation 655-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-nitropyridazin-3(2H)-one

Obtained (37%) from the title product of Preparation 64 following theexperimental procedure described in Preparation 30.

δ(CDCl₃): 0.46 (m, 2H), 0.62 (m, 2H), 1.45 (m, 1H), 2.21 (s, 3H), 4.18(d, 2H), 7.21 (m, 2H), 7.45 (m, 2H).

Preparation 66 4-Nitro-[2,7]naphthyridin-1-ol

To a stirred solution of 2H-[2,7]naphthyridin-1-one (300 mg, 2.05 mmol)(Baldwin, J. J.; Mensler, K.; Ponticello, G. S, J. Org. Chem. 1978,43(25), 4878-80.) in 98% sulfuric acid (2 ml), 60% nitric acid (0.30 ml)was added dropwise and the mixture was warmed to 85° C. during 3 h.Addition, of ice-cold water and basification to pH 7, gave a precipitatewhich was filtered and washed with ethyl ether to yield the titleproduct as a yellow solid (87%).

δ(DMSO-d6): 8.23 (d, 1H), 8.60 (d, 1H), 8.88 (s, 1H), 9.18 (d, 1H).

Preparation 67 4-Amino-[2,7]naphthyridin-1-ol

A mixture of the title compound of Preparation 66 (100 mg, 0.52 mmol)and Ni-Raney (10 mg) in methanol (15 ml) was shaken under hydrogen atroom temperature and 1 atm overnight. Then catalyst was filtered off andthe solvent was removed under reduced pressure to yield the titlecompound (100%).

LRMS: m/Z 162 (M+1)⁺

Preparation 68 4(4-Methoxy-benzoyl)-5-methyl-isoxazole-3-carboxylic acidethyl ester

Obtained as a yellow oil (63%) from1-(4-methoxy-phenyl)-butane-1,3-dione (Popic, V. V. et al., Synthesis1991(3), 19.5) and ethyl chloro(hydroximino)acetate following theexperimental procedure described in Preparation 1. The final product waspurified by column cromatography (n-Hex/EtOAc 9:1 to 1:1).

δ(CDCl₃): 1.18 (t, 3H), 2.58 (s, 3H), 3.90 (s, 3H), 4.20 (q, 2H), 6.95(d, 2H), 7.80 (d, 2H).

Preparation 694-(4-Methoxy-phenyl)-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a white solid (91%) from the title compound of Preparation68 using the experimental procedure described in Preparation 3.

δ(DMSO-d₆): 2.54 (s, 3H), 3.84 (s, 3H), 7.09 (d, 2H), 7.56 (d, 2H).

LRMS (m/z): 258 (M+1)⁺.

Preparation 706-Ethyl-4-(4-methoxyphenyl)-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a yellow solid (79%) from the title compound fromPreparation 69 following the experimental procedure described inPreparation 5.

δ(DMSO-d₆): 1.30 (t, 3H), 2.57 (s, 3H), 3.84 (s, 3H), 4.13 (q, 2H), 7.10(d, 2H), 7.60 (d, 2H).

LRMS (m/z): 286 (M+1)⁺.

Preparation 715-Acetyl-4-amino-2-ethyl-6-(4-methoxy-phenyl)-2H-pyridazin-3-one

Obtained (84%) from the title product of Preparation 70 following theprocedure described in Preparation 14.

δ(DMSO-d₆): 1.29 (t, 3H), 1.75 (s, 3H), 3.81 (s, 3H), 4.10 (q, 2H), 7.03(d, 2H), 7.35 (d, 2H).

Preparation 72 4-(3-Methoxy-benzoyl)-5-methyl-isoxazole-3-carboxylicacid ethyl ester

The title compound was synthesized (76%) from1-(3-methoxy-phenyl)-butane-1,3-dione (Popic, V. V. et al., Synthesis1991 (3); 195) following the procedure described in Preparation 1.

δ(DMSO-d₆): 1.00 (t, 3H), 2.57 (s, 3H), 3.8 (s, 3H), 4.08 (q, 2H),7.25-7.35 (m, 3H), 7.45 (m, 1H).

Preparation 734-(3-Methoxy-phenyl)-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (69%) from the title compound of Preparation 72using the experimental procedure described in Preparation 3.

δ(DMSO-d₆): 2.57 (s, 3H), 3.82 (s, 3H), 7.10 (d, 1H), 7.15-7.20 (m, 2H),7.45 (t, 1H), 12.75 (s, NH).

Preparation 746-Ethyl-4-(3-methoxy-phenyl)-3-methyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (80%) from the title compound of Preparation 73using the experimental procedure described in Preparation 5.

δ(DMSO-d₆): 1.35 (t, 3H), 2.57 (s, 3H), 3.82 (s, 3H), 4.15 (q, 2H),7.10-7.25 (m, 3H), 7.45 (t, 1H).

Preparation 755-Acetyl-4-amino-2-ethyl-6-(3-methoxy-phenyl)-2H-pyridazin-3-one

Obtained as a solid (72%) from the title compound of Preparation 74using the experimental procedure described in Preparation 14.

δ(DMSO-d₆): 1.35 (t, 3H), 1.78 (s, 3H), 3.82 (s, 3H), 4.10 (q, 2H),6.90-7.10 (m, 3H), 7.40 (t, 1H), 7.78 (bs, 2H, NH₂).

Preparation 76 5-Methyl-4-(4-methyl-benzoyl)-isoxazole-3-carboxylic acidethyl ester

The title compound was synthesized (83%) from 1-p-tolyl-butane-1,3-dione(Popic, V. V. et al., Synthesis 1991 (3), 195) following the proceduredescribed in Preparation 1.

δ(CDCl₃): 1.10 (t, 3H), 2.42 (s, 3H), 2.58 (s, 3H), 4.18 (q, 2H), 7.30(d, 2H), 7.70 (d, 2H).

Preparation 77 3-Methyl-4-p-tolyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (38%) from the title compound of Preparation 76using the experimental procedure described in Preparation 3.

δ(CDCl₃): 2.48 (s, 3H), 2.58 (s, 3H), 7.35 (d, 2H), 7.42 (d, 2H).

Preparation 786-Ethyl-3-methyl-4-p-tolyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (89%) from the title compound of Preparation 77using the experimental procedure described in Preparation 5.

δ(CDCl₃): 1.42 (t, 3H), 2.48 (s, 3H), 2.58 (s, 3H), 4.30 (q, 2H), 7.35(d, 2H), 7.45 (d, 2H).

LRMS (m/z): 270 (M+1)⁺.

Retention Time: 9.60 min.

Preparation 79 5-Acetyl-4-amino-2-ethyl-6-p-tolyl-2H-pyridazin-3-one

Obtained as a solid (91%) from the title compound of Preparation 78using the experimental procedure described in Preparation 14.

δ(CDCl₃): 1.42 (t, 3H), 1.80 (s, 3H), 2.42 (s, 3H), 4.28 (q, 2H), 7.30(d, 2H), 7.38 (d, 2H).

LRMS (m/z): 272 (M+1)⁺.

Retention Time: 9.27 min.

Preparation 80 5-Methyl-4-(3-methyl-benzoyl)-isoxazole-3-carboxylic acidethyl ester

The title compound was synthesized (73%) from 1-m-tolyl-butane-1,3-dione(Popic, V. V. et al., Synthesis 1991 (3), 195) following the proceduredescribed in Preparation 1.

δ(CDCl₃): 1.10 (t, 3H), 2.40 (s, 3H), 2.58 (s, 3H), 4.15 (q, 2H),7.30-7.50 (m, 3H), 7.58 (m, 1H).

Preparation 81 3-Methyl-4-m-tolyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (73%) from the title compound of Preparation 80using the experimental procedure described in Preparation 3.

δ(CDCl₃): 2.45 (s, 3H), 2.58 (s, 3H), 7.30-7.50 (m, 4H), 10.05 (bs, 1H,NH).

Preparation 826-Ethyl-3-methyl-4-m-tolyl-6H-isoxazolo[3,4-d]pyridazin-7-one

Obtained as a solid (88%) from the title compound of Preparation 81using the experimental procedure described in Preparation 5.

δ(CDCl₃): 1.42 (t, 3H), 2.45 (s, 3H), 2.58 (s, 3H), 4.30 (q, 2H),7.30-7.50 (m, 4H).

Preparation 83 5-Acetyl-4-amino-2-ethyl-6-m-tolyl-2H-pyridazin-3-one

Obtained as a solid (80%) from the title compound of Preparation 82using the experimental procedure described in Preparation 14.

δ(CDCl₃): 1.42 (t, 3H), 1.80 (s, 3H), 2.42 (s, 3H), 4.28 (q, 2H),7.20-7.40 (m, 4H).

LRMS (m/z): 272 (M+1)⁺.

Retention Time: 9.25 min.

Preparation 84 4-(3-Oxo-butyryl)-benzoic acid methyl ester

A solution of dimethyl terephthalate (10 g, 51.5 mmole) and acetone(4.15 mL, 56.6 mmole) in a mixture of toluene/dimethoxyethane (75 mL/25mL) was added to a suspension of NaH 60% (2.68 g, 66.9 mmole) in drytoluene (25 mL) under argon. The mixture was heated at 100° C. for 4hours. The reaction mixture was cooled to rt and 25 mL of water wereadded. The pH was adjusted to 3-4 with HCl 2N and the mixture was pouredinto water (300 mL). The aqueous mixture was extracted with ethylacetate (3×150 mL), dried over sodium sulphate and evaporated to afforda yellow solid which was purified by column cromatography (n-Hex/EtOAc9:1 to 7:3) to afford the title compound (2.78 g, 25% yield) as a yellowsolid.

δ(CDCl₃): 2.25 (s, 3H), 3.95 (s, 3H), 6.20 (s, 1H), 7.90 (d, 2H), 8.10(d, 2H).

LRMS (m/z): 221 (M+1)⁺.

Retention Time: 9.42 min.

Preparation 854-(4-Methoxycarbonyl-benzoyl)-5-methyl-isoxazole-3-carboxylic acid ethylester

The title compound was synthesized (64%) from the title compound ofPreparation 84 following the procedure described in Preparation 1.

δ(CDCl₃): 1.10 (t, 3H), 2.58 (s, 3H), 3.98 (s, 3H), 4.18 (q, 2H), 7.80(d, 2H), 8.15 (d, 2H).

Preparation 864-(3-Methyl-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazin-4-yl)-benzoicacid methyl ester

Obtained as a solid (91%) from the title compound of Preparation 85using the experimental procedure described in Preparation 3.

δ(CDCl₃): 2.58 (s, 3H), 3.98 (s, 3H), 7.62 (d, 2H), 8.20 (d, 2H), 9.85(bs, 1H. NH).

Preparation 874-(6-Ethyl-3-methy-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazin-4-yl)-benzoicacid methyl ester

Obtained as a solid (70%) from the title compound of Preparation 86using the experimental procedure described in Preparation 5.

δ(CDCl₃): 1.42 (t, 3H), 2.58 (s, 3H), 3.98 (s, 3H), 4.30 (q, 2H), 7.62(d, 2H), 8.20 (d, 2H).

Preparation 884-(4-Acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoicacid methyl ester

Obtained as a solid (97%) from the title compound of Preparation 87using the experimental procedure described in Preparation 14.

δ(CDCl₃): 1.42 (t, 3H), 1.78 (s, 3H), 3.96 (s, 3H), 4.26 (q, 2H), 7.55(d, 2H), 8.14 (d, 2H).

LRMS (m/z): 316 (M+1)⁺.

Retention Time: 8.80 min.

Preparation 89 3-(3-Oxo-butyryl)-benzoic acid methyl ester

A solution of dimethyl isophthalate (12 g, 61.85 mmole) and acetone (5mL, 68 mmole) in a mixture of toluene/dimethoyethane (90 mL/30 mL) wasadded to a suspension of NaH 60% (2.97 g, 74.23 mmole) in dry toluene(30 mL) under argon. The mixture was heated at 100° C. for 4 hours. Thereaction mixture was cooled to rt and 25 mL of water were added. Themixture was poured into water (250 mL) and the pH was adjusted to 3-4with HCl 2N. The aqueous mixture was extracted with ethyl acetate (2×250mL), washed with brine, dried over sodium sulphate and evaporated toafford a yellow solid which was purified by column cromatography(n-Hex/EtOAc 9:1 to 8:2) to afford the title compound (1.78 g, 11%yield) as a yellow solid.

δ(CDCl₃): 2.23 (s, 3H), 3.96 (s, 3H), 6.25 (s, 1H), 7.57 (d, 1H), 8.20(m, 2H), 8.51 (s, 1H).

LRMS (m/z): 221 (M+1)⁺.

Retention Time: 9.32 min.

Preparation 904-(3-Methoxycarbonyl-benzoyl)-5-methyl-isoxazole-3-carboxylic acid ethylester

The title compound was synthesized (62%) from the title compound ofPreparation 89 following the procedure described in Preparation 1.

LRMS (m/z): 318 (M+1)⁺.

Retention Time: 9.07 min.

Preparation 913-(3-Methyl-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazin-4-yl)-benzoicacid methyl ester

Obtained as a solid (80%) from the title compound of Preparation 90using the experimental procedure described in Preparation 3.

LRMS (m/z): 286 (M+1)⁺.

Retention Time: 7.73 min.

Preparation 923-(6-Ethyl-3-methyl-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazin-4-yl)-benzoicacid methyl ester

Obtained as a solid (99%) from the title compound of Preparation 91using the experimental procedure described in Preparation 5.

δ(CDCl₃): 1.42 (t, 3H), 2.58 (s, 3H), 3.96 (s, 3H), 4.26 (q, 2H), 7.65(dd, 1H), 7.80 (d, 1H), 8.20 (d, 1H), 8.25 (s, 1H).

LRMS (m/z): 314 (M+1)⁺.

Retention Time: 9.02 min.

Preparation 933-(4-Acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoicacid methyl ester

Obtained as a solid (98%) from the title compound of Preparation 92using the experimental procedure described in Preparation 14.

δ(CDCl₃): 1.42 (t, 3H), 1.78 (s, 3H), 3.96 (s, 3H), 4.26 (q, 2H),7.45-7.70 (m, 4H), 8.15 (d, 1H), 8.18 (s, 1H).

LRMS (m/z): 316 (M+1)⁺.

Retention Time: 8.68 min.

Preparation 94(3-Methyl-7-oxo-4-phenyl-7H-isoxazolo[3,4-d]pyridazin-6-yl)-acetic acidmethyl ester

Obtained as a white solid (89%) from3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (Renzi, G.;Pinzauti, S., II Farmaco Ed. Sci. 1969, 24, 885-889) and methylbromoacetate following the experimental procedure described inPreparation 5.

δ(CDCl₃): 2.55 (s, 3H), 3.78 (s, 3H), 4.98 (s, 2H), 7.57 (m, 5H).

Preparation 95(4-Acetyl-5-amino-6-oxo-3-phenyl-6H-pyridazin-1-yl)-acetic acid methylester

Obtained as a white solid (99%) from the title compound of Preparation94 following the experimental procedure described in Preparation 14.

δ(CDCl₃): 1.80 (s, 3H), 3.80 (s, 3H), 4.92 (s, 2H), 7.42 (m, 5H).

Preparation 966-Cyclopropylmethyl-3-methylphenyl-6H-isoxazolo[3,4d]pyridazin-7-one

Obtained (91%) from 3-methyl-4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one(Dal Piaz, V. et al. J. Med. Chem. 1997, 40, 1417) and cyclopropylmethylbromide following the experimental procedure described in Preparation 5.

δ(CDCl₃): 0.50 (m, 4H), 1.4 (m, 1H), 2.50 (s, 3H), 4.10 (q, 2H), 7.50(m, 5H).

Preparation 975-Acetyl-2-cyclopropylmethyl-4-nitro-6-phenyl-2H-pyridazin-3-one

Obtained (15.4%) from the title compound of Preparation 96 following theexperimental procedure described in Preparation 30. The crude waspurified by column chromatography (silica gel, hexane/ethyl acetate8:1).

δ(CDCl₃): 0.50 (m, 2H), 0.70 (m, 2H), 1.4 (m, 1H), 2.20 (s, 3H), 4.20(q, 2H), 7.50 (m, 5H).

Preparation 98 5-Nitroquinoline-8-carboxilic acid methyl ester

To a stirred solution of 300 mg (1.375 mmol) of5-nitroquinoline-8-carboxilic acid (Breckenridge, J. G. Et al., CanadianJ. of Research Sect. B; 1947, 25, 49) in DMF (6 mL), 546 mg (3.850 mmol)of iodomethane and 190 mg (1.375 mmol) of potassium carbonate wereadded. The resulting mixture was stirred at room temperature for onehour. Water (10 mL) was added and the product collected by filtration.The residue was washed with water and dried to yield the title compound(250 mg, 78.4%).

LRMS: m/Z 233 (M+1)^(+δ(CDCl) ₃): 4.05 (s, 3H), 7.70 (m, 1H), 8.00 (d,1H), 8.30 (d, 1H), 9.00 (d, 1H), 9.15 (m, 1H).

Preparation 99 5-Aminoquinoline-8-carboxilic acid methyl ester

A mixture of the title compound of Preparation 98 (100 mg, 0.431 mmol)and 10% palladium on charcoal (46 mg) in ethanol (5 mL) was shaken underhydrogen at room temperature and 1 bar for 15 minutes. The catalyst wasfiltered off and the solvent removed under reduced pressure to yield thetitle compound (84 mg, 96%)

LRMS: m/Z 203 (M+1)⁺

EXAMPLES

In the following tables some acronyms have been used with the followingmeanings:

Acronym Meaning 2-Pyr 2-pyridyl 3-Pyr 3-pyridyl 4-Pyr 4-pyridyl PhPhenyl (2-F)Ph 2-fluorophenyl (3-F)Ph 3-fluorophenyl (4-F)Ph4-fluorophenyl (2-Cl)Ph 2-chlorophenyl (3-Cl)Ph 3-chlorophenyl (2-Me)Ph2-methylphenyl or o-tolyl (3-Me)Ph 3-methylphenyl or m-tolyl (4-Me)Ph4-methylphenyl or p-tolyl (2-MeO)Ph 2-methoxyphenyl (3-MeO)Ph3-methoxyphenyl (4-MeO)Ph 4-methoxyphenyl (3-CO₂Me)Ph3-methoxycarbonylphenyl (4-CO₂Me)Ph 4-methoxycarbonylphenyl (4-CO₂H)Ph4-hydroxycarbonylphenyl (4-CH₂OH)Ph 4-hydroxymethylphenyl (3-CN)Ph3-cyanophenyl (4-CN)Ph 4-cyanophenyl (3-NO₂)Ph 3-nitrophenyl 1-Naph1-naphtyl (3,5-diCl)Ph 3,5-dichlorophenyl C₃H₅CH₂ cyclopropylmethyl

In addition in formulas of radicals R3 or R5 depicted in the tables thesymbol X does not symbolize any atoms and has only been used tosymbolize the point of attachment of the radicals.

TABLE 2

Example R1 R2 R3 R4 R5 1 Et H (3-F)Ph Me 3-Pyr 2 Et H (3-Cl)Ph Me 3-Pyr3 Et H (3,5-diCl)Ph Me 3-Pyr 4 Et H 1-Naph Me 3-Pyr 5 Et H (4-CO₂Me)PhMe 3-Pyr 6 Et H (2-F)Ph Me 3-Pyr 7 Et H (2-Cl)Ph Me 3-Pyr 8 Et H(4-CH₂OH)Ph Me 3-Pyr 9 Et H (3-CN)Ph Me 3-Pyr 10 C₃H₅CH₂ H (3-Cl)Ph Me3-Pyr 11 C₃H₅CH₂ H (3,5-diCl)Ph Me 3-Pyr 12 C₃H₅CH₂ H (2-F)Ph Me 3-Pyr13 C₃H₅CH₂ H (2-Cl)Ph Me 3-Pyr 14 C₃H₅CH₂ H (3-CN)Ph Me 3-Pyr 15HOCH₂CH₂ H (4-CO₂Me)Ph Me 3-Pyr 16 HOCH₂CH₂ H (2-F)Ph Me 3-Pyr 17HOCH₂CH₂ H (2-Cl)Ph Me 3-Pyr 18 HOCH₂CH₂ H (3-Cl)Ph Me 3-Pyr 19 Et H(3-Cl)Ph Me 2-Pyr 20 Et H (3-CN)Ph Me 2-Pyr 21 Et H (4-CH₂OH)Ph Me 2-Pyr22 C₃H₅CH₂ H (3-CN)Ph Me 2-Pyr 23 C₃H₅CH₂ H (3-Cl)Ph Me 2-Pyr 24 C₃H₅CH₂H (4-CH₂OH)Ph Me 2-Pyr 25 C₃H₅CH₂ H (3,5-diCl)Ph Me 2-Pyr 26 HOCH₂CH₂ H(3-CN)Ph Me 2-Pyr 27 HOCH₂CH₂ H (3-Cl)Ph Me 2-Pyr 28 HOCH₂CH₂ H(3,5-diCl)Ph Me 2-Pyr 29 HOCH₂CH₂ H (4-CH₂OH)Ph Me 2-Pyr 30 Et H (3-F)PhMe 4-Pyr 31 Et H (3-Cl)Ph Me 4-Pyr 32 Et H 1-Naph Me 4-Pyr 33 Et H(2-Me)Ph Me 4-Pyr 34 Et H (4-CO₂Me)Ph Me 4-Pyr 35 Et H (2-MeO)Ph Me4-Pyr 36 Et H (3-MeO)Ph Me 4-Pyr 37 Et H (2-F)Ph Me 4-Pyr 38 Et H(2-Cl)Ph Me 4-Pyr 39 Et H (3-CN)Ph Me 4-Pyr 40 Et H (4-CH₂OH)Ph Me 4-Pyr41 Et H (4-CO₂H)Ph Me 4-Pyr 42 C₃H₅CH₂ H (2-F)Ph Me 4-Pyr 43 C₃H₅CH₂ H(2-Cl)Ph Me 4-Pyr 44 C₃H₅CH₂ H (3-CN)Ph Me 4-Pyr 45 C₃H₅CH₂ H(4-CH₂OH)Ph Me 4-Pyr 46 C₃H₅CH₂ H (3-Cl)Ph Me 4-Pyr 47 HOCH₂CH₂ H(2-F)Ph Me 4-Pyr 48 HOCH₂CH₂ H (2-Cl)Ph Me 4-Pyr 49 HOCH₂CH₂ H (3-CN)PhMe 4-Pyr 50 HOCH₂CH₂ H (4-CH₂OH)Ph Me 4-Pyr 51 HOCH₂CH₂ H (3-Cl)Ph Me4-Pyr 52 Et H (3-Cl)Ph Me 2-Thienyl 53 Et (3-F)Ph (3-F)Ph Me 3-Pyr 54 Et(4-CO₂Me)Ph (4-CO₂Me)Ph Me 3-Pyr 55 Et (4-CH₂OH)Ph (4-CH₂OH)Ph Me 3-Pyr56 Et (3-NO2)Ph (3-NO2)Ph Me 4-Pyr 57 Et (3-F)Ph (3-F)Ph Me 4-Pyr 58C₃H₅CH₂ (3-Cl)Ph (3-Cl)Ph Me 3-Pyr 59 C₃H₅CH₂ (3,5-diCl)Ph (3,5-diCl)PhMe 3-Pyr 60 HOCH₂CH₂ (4-CO₂Me)Ph (4-CO₂Me)Ph Me 3-Pyr 61 HOCH₂CH₂(3-Cl)Ph (3-Cl)Ph Me 2-Pyr 62 C₃H₅CH₂ (3-Cl)Ph (3-Cl)Ph Me 4-Pyr 63 Et H3-Pyr Me Ph 64 Et H

Me Ph 65 Et H

Me Ph 66 Et H

Me Ph 67 Et H

Me Ph 68 Et H

Me Ph 69 Et H

Me Ph 70 Et H

Me Ph 71 Et H

Me Ph 72 Et H

Me Ph 73 Et H

Me Ph 74 Et H Me Ph 75 Et H

Me Ph 76 Et H

Me Ph 77 Et H

Me Ph 78 Et H 2-Pyr Me Ph 79 Et H

Me Ph 80 Et H

Me Ph 81 Et H

Me Ph 82 Et H

Me Ph 83 Et H

Me Ph 84 Et H

Me Ph 85 Et H

Me Ph 86 Et H

Me Ph 87 Et H

Me Ph 88 Et H 3-Pyr Me (3-Cl)Ph 89 C3H5CH2 H 3-Pyr Me (3-Cl)Ph 90 Et H3-Pyr Me (3-F)Ph 91 iPr H 3-Pyr Me (3-F)Ph 92 C3H5CH2 H 3-Pyr Me (3-F)Ph93 Et H 3-Pyr Me (4-F)Ph 94 Et H (3-Cl)Ph Me

95 Et H (3-Cl)Ph Me

96 Et H (3-F)Ph Me

97 Et (3-Cl)Ph (3-Cl)Ph Me

98 Et (3-F)Ph (3-F)Ph Me

99 Et H (3-MeO)Ph Me

100 Et H (4-CH2OH)Ph Me

101 Et H

Me Ph 102 Et H

Me Ph 103 Et H

Me Ph 104 Et H 3-Pyr Me 4-Pyr 105 Et H

Me 4-Pyr 106 Et H

Me 4-Pyr 107 Et H

Me 4-Pyr 108 Et H

Me 3-Pyr 109 Et H

Me 3-Pyr 110 Et H

Me 3-Pyr 111 Et H

Me 2-Thienyl 112 Et H 3-Pyr Me 2-Thienyl 113 Et H (4-CN)Ph Me 2-Thienyl114 Et H

Me 2-Thienyl 115 Et (4-CN)Ph (4-CN)Ph Me 2-Thienyl 116 C3H5CH2 H

Me 2-Thienyl 117 C3H5CH2 H 3-Pyr Me 2-Thienyl 118 Et H

Me 3-Thienyl 119 Et H (3-Cl)Ph Me 3-Thienyl 120 Et H 3-Pyr Me 3-Thienyl121 Et H (4-CN)Ph Me 3-Thienyl 122 Et H

Me 3-Thienyl 123 Et H

Ph(CH2)2 Ph 124 Et H 3-Pyr Ph(CH2)2 Ph 125 Et H

Ph(CH2)2 Ph 126 Et H

Ph 127 Et H 3-Pyr

Ph 128 Et H (3-Cl)Ph Me

129 Et H (3-Cl)Ph Me

130 Et H (3-Cl)Ph Me

131 Et H 3-Pyr Me 3-Pyr 132 Et H (4-CO2H)Ph Me 3-Pyr 133 Et H

Me Ph 134 Et H

Me 4-Pyr 135 Et H

Me 4-Pyr 136 Et H

Me Ph 137 Et H

Me Ph 138 Et H

Me Ph 139 Et H

Me Ph 140 Et H

Me Ph 141 Et H

Me Ph 142 Et H

Me Ph 143 Et H

Me Ph 144 Et H

Me Ph 145 Et H

Me Ph 146 Et H

Me Ph 147 Et H

CH2OH Ph 148 Et H

Me Ph 149 Et H

Me Ph 150 Et H

Me Ph 151 Et H

Me Ph 152 Et H 2-Thienyl Me Ph 153 Et H

Me Ph 154 Et H

Me Ph 155 Et H

Me Ph 156 Et H

Me Ph 157 Et H

Me Ph 158 Et H

Me Ph 159 Et H

Me Ph 160 Et H

Me Ph 161 Et H

Me Ph 162 Et H

Me Ph 163 Et H

Me (3-F)Ph 164 Et H

Me (4-F)Ph 165 Et H

Me (4-F)Ph 166 Et H

Me (4-F)Ph 167 Et H

Me (4-F)Ph 168 Et H

Me (4-F)Ph 169 C3H5CH2 H

Me (4-F)Ph 170 C3H5CH2 H

Me (4-F)Ph 171 C3H5CH2 H

Me (4-F)Ph 172 C3H5CH2 H

Me (4-F)Ph 173 C3H5CH2 H

Me (4-F)Ph 174 C3H5CH2 H 3-Pyr Me (4-F)Ph 175 Et H

Me (3-Cl)Ph 176 Et H

Me (3-Cl)Ph 177 Et H

Me (3-Cl)Ph 178 Et H

Me Ph 179 Et H

Me Ph 180 Et H

Me (4-MeO)Ph 181 Et H 3-Pyr Me (4-MeO)Ph 182 Et H

Me (4-MeO)Ph 183 Et H

Me (4-MeO)Ph 184 Et H

Me (3-MeO)Ph 185 Et H 3-Pyr Me (3-MeO)Ph 186 Et H

Me (3-MeO)Ph 187 Et H

Me (3-MeO)Ph 188 Et H

Me (4-Me)Ph 189 Et H 3-Pyr Me (4-Me)Ph 190 Et H

Me (4-Me)Ph 191 Et H

Me (4-Me)Ph 192 Et H

Me (4-Me)Ph 193 Et H

Me (3-Me)Ph 194 Et H 3-Pyr Me (3-Me)PH 195 Et H

Me (3-Me)PH 196 Et H

Me (3-Me)PH 197 Et H

Me (4-CO2Me)Ph 198 Et H 3-Pyr Me (4-CO2Me)Ph 199 Et H 3-Pyr Me(4-CO2H)Ph 200 Et H

Me (4-CO2Me)Ph 201 Et H

Me (4-CO2H)Ph 202 Et H 3-Pyr Me (3-CO2Me)Ph 203 Et H 3-Pyr Me (3-CO2H)Ph204 Et H

Me 4-Pyr 205 Et

Me 4-Pyr 206 Et H

Me 3-Pyr 207 Et

Me 3-Pyr 208 CH2CO2Me H

Me Ph 209 CH2CO2H H

Me Ph 210 Et H

Me Ph 211 Et H

Me Ph 212 Et H

Me Ph 213 Et H

Me Ph 214 Et H

Me Ph 215 Et H

Me Ph 216 Et H

Me Ph 217 Et H

Me Ph 218 Et H

Me Ph 219 C3H5CH2 H

Me Ph 220 C3H5CH2 H

Me Ph 221 Et H

Me Ph 222 Et H

Me Ph 223 Et H

Me Ph 224 Et H

Me (3-Cl)Ph 225 Et H

Me (3-Cl)Ph 226 Et H

Me 4-Pyr 227 Et H

Me 3-Pyr 228 Et H

Me Ph 229 C3H5CH2 H

Me (4-F)Ph 230 Et H

Me (4-F)Ph 231 Et H

Me (4-F)Ph 232 C3H5CH2 H

Me (4-F)Ph 233 Et H

Me (3-Cl)Ph 234 Et H

Me Ph 235 Et H

Me (3-Cl)Ph 236 Et H

Me (4-F)Ph 237 Et H

Me (3-F)Ph 238 Et H

Me (3-F)Ph 239 Et H

Me Ph

Example 1 (Scheme 1)5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one

A mixture of the title compound of Preparation 14 (520 mg, 2.0 mmol),3-fluorophenylboronic acid (560 mg, 4.0 mmol), anhydrous cupric acetate(540 mg, 3.0 mmol), triethylamine (0.56 mL, 4.0 mmol) and activatedmolecular sieves (1.6 g, 4 Å) in dry dichloromethane (25 mL) was stirredunder air exposure at room temperature for 48 h. The reaction wasfiltered and the solvent removed under reduced pressure. The resultingresidue was recrystallized from ethyl acetate (202 mg, 30% yield).

m.p. 196.6-197.7° C.

δ(CDCl₃): 1.46 (t, 3H), 1.82 (s, 3H), 4.32 (q, 2H), 6.83 (m, 3H), 7.31(m, 1H), 7.49 (bs, 1H), 7.87 (d, 1H), 8.15 (s, 1H), 8.68 (bs, 2H).

Example 2 (Scheme 1)5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one

Obtained as a solid (27%) from the title compound of Preparation 14 and3-chlorophenylboronic acid following the procedure of Example 1.

m.p. 180.2-180.8° C.

δ(CDCl₃): 1.46 (t, 3H), 1.80 (s, 3H), 4.31 (q, 2H), 6.98 (d, 1H), 7.08(m, 1H), 7.18 (m, 1H), 7.25 (m, 1H), 7.41 (bs, 1H), 7.78 (d, 1H), 8.17(s, 1H), 8.67 (bs, 2H).

Example 3 (Scheme 1)5-Acetyl-4-[(3,5-dichlorophenyl)amino]-2-ethyl-pyridin-3-ylpyridazin-3(2H)-one

Obtained as a solid (30%) from the title compound of Preparation 14 and3,5-dichlorophenylboronic acid following the procedure of Example 1.

m.p. 219.9-220.4° C.

δ(CDCl₃): 1.46 (t, 3H), 1.88 (s, 3H), 4.31 (q, 2H), 6.98 (s, 2H), 7.18(s, 1H), 7.18 (m, 1H), 7.60 (bs, 1H), 8.03 (m, 1H), 8.17 (s, 1H), 8.72(bs, 2H).

Examples 4-9 (Scheme 1)

-   4.    5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-3-ylpyridazin-3(2H)-one-   5. Methyl    4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzoate-   6.    5-Acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   7.    5-Acetyl-4[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   8.    5-Acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-3-ylpyridazin-3(2H)-one-   9.    3-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile

The title compounds were synthesized from the title compound ofPreparation 14 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 2.

TABLE 2 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 4 385 8.1 5 3937.2 6 353 7.1 7 369 7.7 8 365 5.7 9 360 6.8

Examples 10-14 (Scheme 1)

-   10.    5-Acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   11.    5-Acetyl-2-(cyclopropylmethyl)-[(3,5-dichlorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   12.    5-Acetyl-2-(cyclopropylmethyl)-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one-   13.    5-Acetyl-4-[(2-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   14.    3-{[5-Acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile

The title compounds were synthesized from the title compound ofPreparation 17 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 3.

TABLE 3 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 10 395 8.6 11430 9.4 12 379 7.9 13 395 8.5 14 386 7.6

Example 15-18 (Scheme 1)

-   15. Methyl    4-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl]amino}benzoate-   16.    5-Acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   17.    5-Acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   18.    5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 20 and 4-methoxycarbonylphenyl boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 4.

TABLE 4 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 15 408 6.1 16368 5.9 17 384 6.5 18 384 6.9

Example 19 (Scheme 1)5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-2-ylpyridazin-3(2H)-one

Obtained as a solid (27%) from the title compound of Preparation-15 and3-chlorophenylboronic acid following the procedure of Example 1.

LRMS: m/z 369 (M+1)⁺.

δ(CDCl₃): 1.42 (t, 3H), 2.01 (s, 3H), 4.38 (q, 2H), 6.90 (m, 1H), 7.20(m, 4H), 7.82 (m, 3H), 8.42 (d, 1H).

Example 20 (Scheme 1)3-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile

Obtained as a solid (53%) from the title compound of Preparation 15 and3-cyanophenylboronic acid following the procedure of Example 1.

δ(DMSO-d₃): 1.37 (t, 3H), 2.09 (s, 3H), 4.22 (q, 2H), 7.42 (m, 5H), 7.92(m, 2H), 8.49 (m, 1H), 8.89 (s, 1H).

Example 21 (Scheme 1)5-Acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one

Obtained as a solid (13%) from the title compound of Preparation 15 and4-hydroxymethylphenylboronic acid following the procedure of Example 1.

LRMS: m/Z 364 (M+1)⁺.

Retention Time: 4.9 min.

Example 22 (Scheme 1)3-{[5-Acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile

Obtained as a solid (40%) from the title compound of Preparation 18 and3-cyanophenylboronic acid following the procedure of Example 1.

m.p. 168.1-169.6° C.

δ(CD₃OD): 0.49 (m, 2H), 0.59 (m, 2H), 1.36 (m, 1H), 2.11 (s, 3H), 4.13(d, 2H), 7.38 (m, 5H), 7.92 (m, 32H), 8.44 (m, 1H).

Example 23-25 (Scheme 1)

-   23.    5-Acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-2-ylpyridazin-3(2H)-one-   24.    5-Acetyl-2-(cyclopropylmethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one-   25.    5-Acetyl-2-(cyclopropylmethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyridin-2-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 18 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data, and HPLC retention times aresummarized in Table 5.

TABLE 5 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 23 394 8.5 24390 8.9 25 429 9.7

Example 26 (Scheme 1)3-{[5-Acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile

Obtained as a solid (26%) from the title compound of Preparation 21 and3-cyanophenylboronic acid following the procedure of Example 1.

m.p. 194.3-195.0° C.

δ(CD₃OD): 2.10 (s, 3H), 4.01 (t, 2H), 4.40 (t, 2H), 6.90 (m, 1H), 7.35(m, 6H), 7.92 (m, 2H), 8.46 (d, 1H).

Example 27 (Scheme 1)5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one

Obtained as a solid (22%) from the title compound of Preparation 21 and3-chlorophenylboronic acid following the procedure of Example 1.

LRMS: m/Z 385 (M+1)⁺.

Retention Time: 6.0 min.

Examples 28-29 (Scheme 1)

-   28.    5-Acetyl-4-[(3,5-dichlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one-   29.    5-Acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 21 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 6.

TABLE 6 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 28 420 7.2 29381 4.0

Example 30 (Scheme 1)5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (15%) from the title compound of Preparation 16 and3-fluorophenylboronic acid following the procedure of Example 1.

m.p. 195.1-195.9° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.87 (s, 3H), 4.18 (q, 2H), 6.88 (m, 3H), 7.28(m, 1H), 7.31 (d, 2H), 8.58 (d, 2H), 9.24 (so 1H).

Example 31 (Scheme 1)5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (68%) from the title compound of Preparation 16 and3-chlorophenylboronic acid following the procedure of Example 1.

m.p. 176.4-177.0° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.87 (s, 3H), 4.18 (q, 2H), 7.01 (m, 3H), 7.29(m, 3H), 8.60 (m, 2H), 9.24 (s, 1H).

Example 32 (Scheme 1)5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (53%) from the title compound of Preparation 16 andnaphthalene-1-boronic acid following the procedure of Example 1.

m.p. 177.6-179.3° C.

δ(DMSO-d₆, 75° C.): 1.37 (m, 6H), 4.23 (q, 2H), 7.23 (m, 3H), 7.37 (m,1H), 7.54 (m, 2H), 7.70 (m, 1H), 7.92 (m, 1H), 8.01 (m, 1H), 8.55 (m,2H), 8.89 (s, 1H).

Example 33 (Scheme 1)5-Acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (17%) from the title compound of Preparation 16 and2-methylphenylboronic acid following the procedure of Example 1.

m.p. 187.8-189.4° C.

δ(CD₃OD): 1.42 (t, 3H), 1.60 (s, 3H), 2.29 (s, 3H), 4.30 (q, 2H), 7.02(m, 1H), 7.14 (m, 2H), 7.25 (m, 1H), 7.40 (m, 2H), 8.54 (m, 2H).

Examples 34-40 (Scheme 1)

-   34. Methyl    4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoate-   35.    5-Acetyl-2-ethyl-4-[(2-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   36.    5-Acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   37.    5-Acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   38.    5-Acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   39.    3-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   40.    5-Acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 16 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 7.

TABLE 7 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 34 392 7.0 35364 6.9 36 364 6.9 37 352 6.8 38 368 7.5 39 359 6.4 40 364 5.4

Example 41 (Hydrolisis No Scheme)4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoicacid

To a stirred solution of the title product of example 34 (0.38 g, 0.97mmol) in 40 mL of a 3:2 MeOH/THF mixture a solution of lithium hydroxide(0.25 g, 5.88 mmol) in 4 mL of water was added and the mixture wasstirred at room temperature overnight. It was acidified with HCl 2Nuntil pH 6 and it was extracted with dichloromethane and washed withwater and brine. It was dried on Na2SO4 and solvent removed to yield acrude product that was purified by column chromatography on SiO2 usingCH2Cl2/MeOH as eluent. The title product was obtained in a 16% yield.

m.p. 251.6-252.6° C.

δ(DMSO-d₆): 1.34 (m, 3H), 1.93 (s, 3H), 4.20 (q, 2H), 7.08 (d, 2H), 7.33(d, 2H), 7.79 (d, 2H), 8.60 (d, 2H), 9.38 (s, 1H).

Examples 42-46 (Scheme 1)

-   42.    5-Acetyl-2-(cyclopropylmethyl)-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one-   43.    5-Acetyl-4-[(2-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   44.    3-{[5-Acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   45.    5-Acetyl-2-(cyclopropylmethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one-   46.    5-Acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 19 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 8.

TABLE 8 ESI/MS m/e Retention (M + H)⁺ Time (min) 42 378 7.8 43 394 8.544 385 7.4 45 390 6.4 46 394 8.4

Examples 47-51 (Scheme 1)

-   47.    5-Acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   48.    5-Acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one-   49.    3-{[5-Acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile-   50.    5-Acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one-   51.    5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 22 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 9.

TABLE 9 ESI/MS m/e Retention (M + H)⁺ Time (min) 47 368 5.5 48 384 6.249 375 5.2 50 380 4.3 51 384 6.4

Example 52 (Scheme 1)5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one

Obtained as a solid (20%) from the title compound of Preparation 26 and3-chlorophenylboronic acid following the procedure of Example 1.

LRMS: m/Z 374 (M+1)⁺.

δ(CDCl₃): 1.46 (t, 3H), 1.88 (s, 3H), 4.29 (q, 2H), 7.00 (m, 3H), 7.08(m, 1H), 7.26 (m, 2H), 7.27 (m, 1H), 7.98 (m, 1H).

Examples 53-55 (Scheme 1)

-   53.    5-Acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   54.    5-Acetyl-4-[bis-4-methoxycarbonylphenyl)-amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one-   55.    5-Acetyl-4-{bis[4-(hydroxymethyl)phenyl]amino}-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 14 and an excess of the corresponding arylboronic acidfollowing the experimental procedure described in example 1. The ESI/MSdata and HPLC retention times are summarized in Table 10.

TABLE 10 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 53 446 8.9 54526 8.7 55 470 6.2

Examples 56-57 (Scheme 1)

-   56.    5-Acetyl-4-[bis(3-nitrophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one-   57.    5-acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 16 and an excess of the corresponding arylboronic acidfollowing the experimental procedure described in example 1. The ESI/MSdata and HPLC retention times are summarized in Table 11.

TABLE 11 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 56 501 8.5 57447 8.9

Examples 58-59 (Scheme 1)

-   58.    5-Acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one-   59.    5-Acetyl-4-[bis(3,5-dichlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 17 and an excess of the corresponding arylboronic acidfollowing the experimental procedure described in example 1. The ESI/MSdata and HPLC retention times are summarized in Table 12.

TABLE 12 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 58 505 10.2 59574 11.0

Example 60 (Scheme 1)5-Acetyl-4-[bis(4-methoxycarbonylphenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one

The title compound was synthesized from the title compound ofPreparation 20 and an excess of 4-methoxycarbonylphenylboronic acidfollowing the experimental procedure described in example 1.

LRMS: m/Z 542 (M+1)⁺.

Retention Time: 8.0 min.

Example 61 (Scheme 1)5-Acetyl-4-[bis(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one

The title compound was synthesized from the title compound ofPreparation 21 and an excess of 3-chlorophenylboronic acid following theexperimental procedure described in example 1.

LRMS: m/Z 495 (M+1)⁺.

Retention Time: 9.6 min.

Example 62 (Scheme 1)5-Acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one

The title compound was synthesized from the title compound ofPreparation 19 and an excess of 3-chlorophenylboronic acid following theexperimental procedure described in example 1;

LRMS: m/Z 505 (M+1)⁺.

Retention Time: 10.2 min.

Example 63 (Scheme 2)5-Acetyl-2-ethyl-6-phenyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one

To a stirred solution of 200 mg (0.7 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (10 mL), 3-aminopyridine (0.098mg, 1.04 mmol) was added portionwise. The resulting mixture was stirredat room temperature for five hours. The solvent was evaporated and theresidue purified by column chromatography (silica gel,dichloromethane/methanol 97:3) to yield the title compound (60 mg, 26%yield).

m.p. 185.6-186.3° C.

δ(DMSO-d₆): 1.34 (m, 3H), 1.72 (s, 3H), 4.18 (q, 2H), 7.29 (m, 3H), 7.41(m, 4H) 8.26 (d, 1H), 8.33 (d, 1H), 9.10 (s, 1H).

Example 64 (Scheme 2)5-Acetyl-4-[(3,5-dichloropyridin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one

To a stirred suspension of 50 mg (1.25 mmol) of sodium hydride in 5 mlof THF, 100 mg (0.62 mmol) of 4-amino-3,5-dichloropyridine in 5 ml ofTHF was added. The mixture was allowed stirring 30 minutes at roomtemperature and then cooled to 0° C. 150 mg (0.52 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 10 ml of THF was added. The reactionwas allowed to warm to room temperature and to continue stirring for 12hours. The mixture was acidified with 2N HCl to pH 2. Ethyl acetate wasadded and the organic layer was washed with water, brine, dried overNa₂SO₄ anhydride and evaporated. The residue obtained (210 mg) waspurified by column chromatography (silica gel, hexane/ethyl acetate 1:1)to yield the title compound (35 mg, 16.7% yield).

m.p. 195.5-197.1° C.

δ(CDCl₃): 1.40 (m, 3H), 1.85 (s, 3H), 4.10 (q, 2H), 7.45 (bs, 5H), 8.40(s, 2H), 8.80 (s, 1H).

Example 65 (Scheme 2)5-Acetyl-2-ethyl-6-phenyl-4-(pyrazin-2-ylamino)pyridazin-3(2H)-one

To a stirred solution of 75 mg (0.261 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 37 mg (0.392 mmol) ofaminopyrazine was added. The resulting mixture was stirred at roomtemperature during 3 days and the final product was collected byfiltration and washed with diethylether to yield the title compound (12mg, 13.6% yield).

m.p. 228.9-229.7° C.

δ(DMSO-d₆): 1.34 (m, 3H), 1.84 (s, 3H), 4.21 (q, 2H), 7.34 (m, 2H), 7.48(m, 3H) 8.12 (m, 2H), 8.67 (s, 1H), 9.93 (s, 1H).

Example 66 (Scheme 2)5-Acetyl-2-ethyl-6-phenyl-4-(pyrimidin-2-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.348 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanol, 430 mg (4.524 mmol) of2-aminopyrimidine was added. The resulting mixture was stirred at 50° C.during five days and the final product was collected by filtration andwashed with diethylether to yield the title compound (42 mg, 35.6%yield).

m.p. 197.1-198.3° C.

δ(DMSO-d₆): 1.33 (m, 3H), 1.96 (s, 3H), 4.19 (q, 2H), 7.02 (m, 1H), 7.37(m, 2H) 7.49 (m, 3H), 8.52 (m, 2H), 9.02 (s, 1H).

Example 67 (Scheme 2)5-Acetyl-2-ethyl-6-phenyl(quinolin-8-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.348 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (pal Piaz, V etal., J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanol, 75 mg (0.522mmol) of 8-aminoquinoline was added. The resulting mixture was stirredat room temperature for two hours and the final product was collected byfiltration and washed with diethylether to yield the title compound (100mg, 74.6% yield).

m.p. 179.2.1-180.3° C.

δ(CDCl₃): 1.49 (m, 3H), 1.75 (s, 3H), 4.34 (q, 2H), 7.25 (m, 1H), 7.45(m, 7H) 7.56 (m, 1H), 8.17 (dd, 1H), 8.92 (d, 1H), 9.55 (s, 1H).

Example 68 (Scheme 2)5-Acetyl-2-ethyl-4-[(5-nitropyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one

To a solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 77 mg (0.556 mmol) of2-amino-5-nitropyridine was added. The resulting mixture was irradiatedin microwave oven for seven hours at 120° C. The final product wascollected by filtration and washed with diethylether to yield the titlecompound (36 mg, 34.3% yield).

m.p. 200.3-201.1° C.

δ(DMSO-d₆): 1.35 (m, 3H), 1.92 (s, 3H), 4.22 (q, 2H), 7.39 (m, 3H), 7.49(m, 3H), 8.41-8.45 (dd, 1H), 8.92 (d, 1H), 10.34 (s, 1H).

Example 69 (Scheme 2)5-Acetyl-2-ethyl-4-(1H-indol-4-ylamino)-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg (0.417 mmol) of4-aminoindole was added. The resulting mixture was stirred at roomtemperature for one hour and the final product was collected byfiltration and washed with diethylether to yield the title compound (83mg, 79.8% yield).

m.p. 223.2-224.9° C.

δ(CDCl₃): 1.27 (s, 3H), 1.36 (m, 3H), 4.19 (q, 2H), 6.33 (s, 1H),6.66-6.67 (d, 1H), 6.95 (m, 1H), 7.25 (m, 3H), 7.31-7.37 (m, 4H), 8.76(s, 1H), 11.20 (s, 1H).

Examples 70-78

-   70.    5-Acetyl-4-(1,3-benzothiazol-6-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one-   71.    5-Acetyl-2-ethyl-6-phenyl-4-(thianthren-1-ylamino)pyridazin-3(2H)-one-   72. Methyl    3-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylate-   73.    5-Acetyl-2-ethyl-4-[(4-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   74.    5-Acetyl-2-ethyl-6-phenyl-4-(1H-1,2,4-triazol-5-ylamino)pyridazin-3(2H)-one-   75.    5-Acetyl-2-ethyl-4-[(6-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   76.    5-Acetyl-2-ethyl-4-(2H-indazol-5-ylamino)-6-phenylpyridazin-3(2H)-one-   77. Methyl    4-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-3-carboxylate-   78.    5-Acetyl-2-ethyl-6-phenyl-4-(pyridin-2-ylamino)pyridazin-3(2H)-one

The title compounds were synthesized from5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) and the corresponding aniline oraminopyridine following the procedure of Example 67. The ESI/MS data andHPLC retention times are summarized in Table 13.

TABLE 13 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 70 390 8.2 71471 10.5 72 397 9.1 73 348 5.0 74 324 7.5 75 364 8.3 76 373 7.7 77 3988.8 78 335 4.8

Example 79 (Hydrolisis: No Scheme)3-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylicacid

The title compound was synthesized from the title compound of example 72following the experimental procedure described in example 41.

LRMS: m/Z 383 (M+1)⁺.

Retention Time: 8.5 min.

Example 80 (Scheme 2)5-Acetyl-2-ethyl-4-[(3-methylcinnolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of3-methylcinnolin-5-amine was added. The resulting mixture was stirred atroom temperature for one day. The final product was collected byfiltration and purified by column chromatography (silica gel, ethylacetate/hexane 2:1) to yield the title compound (65 mg, 58.6% yield).

m.p. 235.4-237.7° C.

δ(DMSO-d₆): 1.37 (m, 3H), 1.41 (s, 3H), 2.91 (s, 3H), 4.22 (q, 2H), 7.25(m, 2H) 7.35-7.40 (m, 3H), 7.53 (d, 1H), 7.67-7.72 (t, 1H), 8.10 (s,1H), 8.24 (d, 1H), 9.19 (s, 1H).

Example 81 (Scheme 2)5-Acetyl-2-ethyl-4-[(2-methylquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of2-methylquinolin-8-amine was added. The resulting mixture was stirred atroom temperature for one hour and the final product was collected byfiltration and washed with diethylether to yield the title compound (97mg, 93.3% yield).

m.p. 172.2-172.6° C.

δ(DMSO-d₆): 1.22 (m, 3H), 1.52 (s, 3H), 2.54 (s, 3H), 4.07 (q, 2H), 7.02(d, 1H), 7.21-7.30 (m, 6H), 7.35 (d, 1H), 7.46 (d, 1H), 8.13 (d, 1H),9.15 (s, 1H).

Example 82 (Scheme 2)5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 60 mg (0.417 mmol) of5-aminoquinoline was added. The resulting mixture was stirred at roomtemperature for four hours and the final product was collected byfiltration and washed with diethylether to yield the title compound (80mg, 74.8% yield).

m.p. 219.9-221.1° C.

δ(DMSO-d₆): 1.31 (s, 3H), 1.38 (m, 3H), 4.22 (q, 2H), 7.24 (m, 2H),7.34-7.38 (m, 4H), 7.55-7.63 (m, 2H), 7.86 (d, 1H), 8.42 (d, 1H), 8.92(d, 1H), 9.19 (s, 1H).

Example 83 (Scheme 2)5-Acetyl-2-ethyl-4-(1H-indol-5-ylamino)-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (9.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg (0.417 mmol) of5-aminoindole was added. The resulting mixture was stirred at roomtemperature for one hour and the final product was collected byfiltration and washed with diethylether to yield the title compound (97mg, 93.3% yield).

m.p. 242.6-243.1° C.

δ(DMSO-d₆): 1.34 (m, 3H), 1.47 (s, 3H), 4.17 (q, 2H), 6.33 (bs, 1H),6.83 (d, 1H), 7.24-7.37 (m, 8H), 8.77 (s, 1H), 11.09 (s, 1H).

Example 84 (Scheme 2)5-Acetyl-2-ethyl-4-(isoquinolin-5-ylamino)-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 60 mg (0.417 mmol) of5-isoquinolinamine was added. The resulting mixture was stirred at roomtemperature for three days. The final product was collected byfiltration and purified by column chromatography (silica gel, ethylacetate/hexane 7:3) to yield the title compound (20 mg, 12.4% yield).

δ(DMSO-d₆): 1.31 (s, 3H), 1.38 (m, 3H), 4.22 (q, 2H), 7.24 (m, 2H), 7.38(m, 3H), 7.53 (m, 2H), 7.85 (d, 1H), 7.97 (d, 1H), 8.53 (d, 1H), 9.18(s, 1H), 9.32 (s, 1H).

Example 85 (Scheme 2)5-Acetyl-2-ethyl-4-[(6-methoxyquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 73 mg (0.417 mmol) of8-amino-6-methoxyquinoline was added. The resulting mixture was stirredat room temperature for two hours and the final product was collected byfiltration and washed with diethylether to yield the title compound (88mg, 76.5% yield).

m.p. 183.1-184.0° C.

δ(DMSO-d₆): 1.34 (m, 3H), 1.68 (s, 3H), 3.84 (s, 3H), 4.21 (q, 2H), 6.81(s, 1H), 7.08 (s, 1H), 7.36-7.46 (m, 5H), 7.53-7.57 (m, 1H), 8.27 (d,1H), 8.73 (d, 1H), 9.31 (s, 1H).

Example 86 (Scheme 2)5-Acetyl-4-[(5-bromoquinolin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one

To a stirred solution of 40 mg (0.139 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL),8-amino-5-bromoquinoline (47 mg, 0.209 mmol) was added. The resultingmixture was stirred at room temperature for five days and heated at 50°C. during four days. The solvent was evaporated and the residue purifiedby column chromatography (silica gel, hexane/ethyl acetate 4:1) to yieldthe title compound (16 mg, 25% yield).

m.p. 148.1-149.0° C.

δ(DMSO-d₆): 1.35 (m, 3H), 1.70 (s, 3H), 4.20 (q, 2H), 7.13 (d, 1H),7.39-7.46 (m, 5H), 7.76 (m, 1H), 7.84 (d, 1H), 8.50 (d, 1H), 8.99 (d,1H), 9.41 (s, 1H).

Example 87 (Scheme 2)5-Acetyl-2-ethyl-4-[(4-methylpyrimidin-2-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL),2-amino-4-methylpyrimidine (46 mg, 0.417 mmol) was added. The resultingmixture was stirred at 50° C. during five days. The solvent wasevaporated and the residue purified by column chromatography (silicagel, hexane/ethyl acetate 2:1) to yield the title compound (11 mg, 11.3%yield).

LRMS: m/Z 350 (M+1)⁺.

Retention Time: 7.4 min.

Example 88 (Scheme 2)5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one

Obtained from5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (DalPiaz, V et al., J. Med. Chem. 1997, 40, 1417) and pyridin-3-ylaminefollowing the procedure of Example 67. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 369 (M+1)⁺.

Retention Time: 8.2 min.

Example 89 (Scheme 2)5-Acetyl-6-(3-chlorophenyl)-2-cyclopropylmethyl-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one

Obtained from the title compound of preparation 40 and pyridin-3-ylaminefollowing the procedure of Example 67. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 395 (M+1)⁺.

Retention Time: 9.1 min.

Example 90 (Scheme 2)5-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one

Obtained from the title compound of preparation 36 and pyridin-3-ylaminefollowing the procedure of Example 67. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 353(M+1)⁺.

Retention Time: 7.4 min.

Example 91 (Scheme 2)5-Acetyl-6-(3-fluorophenyl)-2-isopropyl-4-pyridin-3-ylamino)-pyridazin-3(2H)-one

Obtained from the title compound of preparation 38 and pyridin-3-ylaminefollowing the procedure of Example 67. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 367 (M+1)⁺.

Retention Time: 8.3 min.

Example 92 (Scheme 2)5-Acetyl-2-cyclopropylmethyl-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one

Obtained from the title compound of preparation 37 and pyridin-3-ylaminefollowing the procedure of Example 67. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 379 (M+1)⁺.

Retention Time: 8.4 min.

Example 93 (Scheme 2) 5-Acetyl-6-(4-fluorophenyl)-2-ethyl4-(pyridin-3-ylamino)-pyridazin-3(2H)-one

Obtained from the title compound of preparation 30 and pyridin-3-ylaminefollowing the procedure of Example 67. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 353 (M+1)⁺.

Retention Time: 7.4 min.

Example 945-Acetyl-6-(1H-benzoimidazol-2-yl)-4-(3-chloro-phenylamino)-2-ethyl-2H-pyridazin-3-one

To 10 mL of dry toluene under nitrogen, trimethylalumminium (1.05 mL ofa 2M solution in toluene) was added and the solution was cooled down to0° C. Then 1,2-diaminobenzene (68 mg, 0.63 mmol) was added in portionsand the mixture was stirred at 0° C. for 30 min and at 15° C. for 1hour. Then, the title product of preparation 45 (150 mg, 0.42 mmol) wasadded in one portion and the final mixture was refluxed for 1.5 hours.Then it was let to warm to room temperature and water and methanol werecarefully added. The white precipitate thus formed was filtered and themother liquor was neutralized with HCl 2N and solvent was removed.Finally the residue was partiotioned between water and dichloromethaneand the organic layer was washed with brine. Dried and solvent removedto yield a crude product that was purified by column chromatography.

LRMS: m/Z 408 (M+1)⁺.

Retention Time: 8.0 min.

δ(CDCl₃): 1.41 (t, 3H), 2.01 (s, 3H), 4.38 (q, 2H), 6.85 (m, 2H), 7.10(m, 5H), 7.38 (s, 1H), 7.78 (s, 1H)

Examples 95-96 (Scheme 1)

-   95.    5-Acetyl-6-benzooxazol-2-yl-4-(3-chlorophenylamino)-2-ethyl-pyridazin-3(2H)-one-   96.    5-Acetyl-6-benzooxazol-2-yl-4-(3-fluorophenylamino)-2-ethyl-pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 48 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 14.

TABLE 14 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 95 408 9.7 96392 9.4

Examples 97-98 (Scheme 1)

-   97.    5-Acetyl-6-benzooxazol-2-yl-4-[bis-(3-chlorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one-   98.    5-Acetyl-6-benzooxazol-2-yl-4-[bis-(3-fluorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 48 and an excess of the corresponding arylboronic acidfollowing the experimental procedure described in example 1. The ESI/MSdata and HPLC retention times are summarized in Table 15.

TABLE 15 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 97 519 10.9 98486 10.4

Examples 99-100

-   99.    5-Acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-[(3-methoxyphenyl)amino]pyridazin-3(2H)-one-   100.    5-Acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 48 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 16.

TABLE 16 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 99 405 9.4 100405 8.2

Example 1015-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-phenylpyridazin-3(2H)-one

A mixture of the title compound of Preparation 49 (2.2 g, 8.56 mmol),4-bromoisoquinoline (2.14 g, 10.3 mmol), anhydrous cuprous iodide (170mg, 0.89 mmol) mmol), N,N′-dimethylethylenediamine (0.185 ml, 0.89 mmol)and potassium carbonate (1.73 g, 12.5 mmol) in dry dioxane under argonwas stirred in a sealed tube at 130° C. for 24 h. The reaction wasfiltered and the solvent removed under reduced pressure. The resultingresidue was purified by flash column cromathography (SiO₂,dichloromethane-ethyl acetate) to yield the title product (450 mg, 14%yield).

m.p. 215.9-216.5° C.

δ(CDCl₃): 1.43 (s, 3H), 1.48 (t, 3H), 4.34 (q, 2H), 7.35 (m, 5H), 7.70(m, 1H), 7.79 (m, 1H), 8.08 (m, 2H), 8.29 (m, 2H), 9.16 (s, 1H).

Examples 102-103

-   102.    5-Acetyl-2-ethyl-4-(1,6-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one-   103.    5-Acetyl-2-ethyl-4-[(5-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 49 and the corresponding bromide following the procedure ofExample 101. The ESI/MS data and HPLC retention times are summarized inTable 17.

TABLE 17 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 102 386 15*103 365  7.9 *Chromatografic method B.

Example 1045-Acetyl-2-ethyl-6-pyridin-4-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained as a yellow solid (69%) from the title compound of Preparation16 and 3-bromopyridine following the procedure of Example 101.

LRMS: m/Z 336 (M+1)⁺.

Retention Time: 6 min*. *Chromatografic method B.

δ(CDCl₃): 1.45 (t, 3H), 1.79 (s, 3H), 4.30 (q, 2H), 7.30 (m, 3H), 7.41(m, 1H), 8.42 (m, 3H), 8.68 (m, 2H).

Example 1055-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (31%) from the title compound of Preparation 16 and3-bromo-4-methylpyridine following the procedure of Example 101.

m.p. 207.8-208.9° C.

δ(DMSO-d₃): 1.33 (t, 3H), 1.68 (s, 3H), 2.21 (s, 3H), 4.16 (m, 2H), 7.22(m, 1H), 7.27 (m, 2H), 8.17 (m, 2H), 8.57 (m, 2H), 8.82 (m, 1H).

Examples 106-107

-   106.    5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-4-ylpyridazin-3(2H)-one-   107.    5-Acetyl-2-ethyl-6-pyridin-4-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 16 and the corresponding bromide following the procedure ofExample 101. The ESI/MS data and HPLC retention times are summarized inTable 18.

TABLE 18 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 106 386 6.4107 388 7.9

Example 1085-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one

Obtained as a solid (21%) from the title compound of Preparation 14 and3-bromo-4-methylpyridine following the procedure of Example 101.

m.p. 194.7-195.4° C.

δ(DMSO-d₃): 1.35 (t, 3H), 1.52 (s, 3H), 2.22 (s, 3H), 4.20 (q, 2H), 7.24(d, 1H), 7.40 (m, 1H), 7.68 (m, 1H), 8.25 (m, 2H), 8.48 (s, 1H), 8.58(m, 1H), 8.87 (s, 1H).

Examples 109-110

-   109.    5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-3-ylpyridazin-3(2H)-one-   110.    5-Acetyl-2-ethyl-6-pyridin-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)one

The title compounds were synthesized from the title-compound ofPreparation 14 and the corresponding bromide following the procedure ofExample 101. The ESI/MS data and HPLC retention times are summarized inTable 19.

TABLE 19 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 109 386  6.6110 389 15* *Chromatografic method B.

Example 1115-Acetyl-2-ethyl-4-quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one

Obtained as a solid (50%) from the title compound of Preparation 26 andquinoline-5-boronic acid following the procedure of Example 1.

m.p. 214.2-215.0° C.

δ(CDCl₃): 1.43 (t, 3H), 1.51 (s, 3H), 4.32 (q, 2H), 6.85 (m, 1H), 6.90(m, 1H), 7.36 (m, 2H), 7.52 (m, 1H), 7.64 (m, 1H), 8.05 (m, 2H), 8.42(m, 1H), 9.00 (m, 1H).

Examples 112-114

-   112.    5-Acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one-   113.    4-[(5-Acetyl-2-ethyl-3-oxo-6-thien-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   114.    5-Acetyl-2-ethyl-6-thien-2-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 26 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 20.

TABLE 20 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 112 341 12*113 365  8.9 114 394 10.2

Example 1155-Acetyl-4-(bis(4-cyanophenyl)amino)-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one

Obtained as a solid from the title, compound of Preparation 26 and anexcess of 4-cyanophenylboronic acid following the experimental proceduredescribed in Example 1.

LRMS: m/Z 466 (M+1)⁺.

Retention Time: 9.9 min.

Examples 116-117

-   116.    5-Acetyl-2-(cyclopropylmethyl)-4-(quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one-   117.    5-Acetyl-2-(cyclopropylmethyl)-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 51 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 21.

TABLE 21 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 116 417 15*117 367 14* *Chromatografic method B.

Example 1185-Acetyl-2-ethyl-4-(quinolin-5-ylamino)-6-thien-3-ylpyridazin-3(2H)-one

Obtained as a solid (52%) from the title compound of Preparation 55 andquinoline-5-boronic acid following the procedure of Example 1.

m.p. 186.6-187.3° C.

δ(CDCl₃): 1.45 (s, 3H), 1.51 (t, 3H), 4.34 (q, 2H), 7.11 (m, 1H), 7.30(m, 3H), 7.52 (m, 1H), 7.65 (m, 1H), 8.08 (m, 2H), 8.43 (m, 1H), 8.99(m, 1H).

Examples 119-122

-   119.    5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one-   120.    5-Acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-3-ylpyridazin-3(2H)-one-   121.    4-[(5-Acetyl-2-ethyl-3-oxo-6-thien-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile-   122.    5-Acetyl-2-ethyl-6-thien-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 55 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 22.

TABLE 22 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 119 374 9.4120 341 6.9 121 365 9.3 122 394 10.1

Example 1232-Ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-quinolin-5-ylamino)pyridazin-3(2H)-one

Obtained as a solid (50%) from the title compound of Preparation 58 andquinoline-5-boronic acid following the procedure of Example 1.

m.p. 164.0-165.8° C.

δ(CDCl₃): 1.48 (t, 3H), 1.79 (t, 2H), 2.01 (t, 2H), 4.35 (q, 2H), 6.42(m, 2H), 7.05 (m, 3H), 7.32 (m, 6H), 7.51 (m, 1H), 7.64 (m, 1H), 8.09(m, 2H), 8.46 (m, 1H), 9.00 (m,

Examples 124-125

-   124.    2-Ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one-   125.    2-Ethyl-4-(isoquinolin-4-ylamino)-6-phenyl-5-(3-phenylpropanoyl)pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 58 and the corresponding bromide following the procedure ofExample 101. The ESI/MS data and HPLC retention times are summarized inTable 23.

TABLE 23 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 124 425 17*125 475 17*

Examples 126-127

-   126.    2-Ethyl-6-phenyl-4-(quinolin-5-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one-   127.    2-Ethyl-6-phenyl-4-(pyridin-3-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 59 and the corresponding boronic acid following theprocedure of Example 1. The ESI/MS data and HPLC retention times aresummarized in Table 24.

TABLE 24 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 126 481 17*127 431 16* *Chromatografic method B.

Example 1285-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(1H-imidazo[4,5-b]pyridin-2-yl)pyridazin-3(2H)-one

Obtained as a solid (7%) from the title compound of Preparation 45 and2,3-diaminopyridine acid following the experimental procedure describedin example 94.

LRMS: m/Z 409 (M+1)⁺.

Retention Time: 6.3 min.

Example 1295-Acetyl-6-(1,3-benzothiazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one

Obtained as a solid (22%) from the title compound of Preparation 45 and2-aminobenzenethiol following the experimental procedure described inexample 94.

LRMS: m/Z 425 (M+1)⁺.

Retention Time: 10.5 min.

Example 1305-Acetyl-6-(1-benzofuran-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one

Obtained as a solid (31%) from the title compound of Preparation 63 and3-chlorophenyl boronic acid following the procedure of Example 1.

LRMS: m/Z 408 (M+1)⁺.

Retention Time: 10.2 min.

Example 1315-Acetyl-2-ethyl-6-pyridin-3-yl-4-pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained as a solid from the title compound of Preparation 14 and3-pyridineboronic acid following the procedure of Example 1.

LRMS: m/Z 334 (M+1)⁺.

Retention Time: 4.9 min.

Example 1324-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzoicacid

Obtained as a solid from the title compound of Example 5 following theprocedure of Example 41.

LRMS: m/Z 379 (M+1)⁺.

Retention Time: 6.1 min.

Example 1335-Acetyl-2-ethyl-4-[(1-oxidopyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 50-55% m-chloroperbenzoic acid (1.30 mg, 0.38mmol aprox.) in dichloromethane (2 ml); a solution of the title productof example 63 (126 mg, 0.38 mmol) in dichloromethane (2 ml) was addeddropwise and the resulting mixture was stirred at rt overnight. Then itwas diluted with dichloromethane and poured onto 10% sodium sulphitesolution. The organic layer was further washed with saturated sodiumbicarbonate solution and brine. It was then dried and solvent removed toyield a crude product that was purifiedd by preparative HPLC/MS.

LRMS: m/Z 351 (M+1)⁺.

Retention Time: 6.9 min.

Example 134 Ethyl3-(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-ylamino)benzoate

Obtained as a solid (67%) from the title compound of Preparation 16 and3-ethoxycarbonylphenylboronic acid following the procedure of Example 1.

LRMS: m/Z 407 (M+1)⁺. δ(CDCl₃): 1.38 (t, 3H), 1.46 (t, 3H), 1.58 (s,3H), 4.35 (m, 4H), 7.28 (m, 3H), 7.41 (m, 1H), 7.70 (s, 1H), 7.88 (m,1H), 8.29 (s, 1H), 8.63 (m, 2H).

Example 1353-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzamide

To a 0° C. precooled solution of saturated ammonia in THF (2 ml) underargon, trimethylaluminium (0.307 mL, 0.615 mmol) was added and themixture was stirred for 30 min. Then, a solution of the title compoundof Example 134 (50 mg, 0.123 mmol) in dry THF (1 mL) was added dropwiseand the final mixture was stirred at rt overnight. Some moretrimethylalumminium (0.307 mL, 0.615 mmol) was added and the mixture wasrefluxed overnight. It was then let to cool down and water was added.The solid thus formed was removed by filtration and the mother liquorwas diluted with water, neutralized with 0.1 M HCl and extracted withdichloromethane. The organic layer was washed with water and brine anddried. Finally, solvent was removed to yield a crude product that waspurified by preparative HPLC/MS (20% yield).

LRMS: m/Z 78 (M+1)⁺.

Retention Time: 5.1 min.

Example 1365-Acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-b]pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained, (27%) from5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) and thieno[2,3-b]pyridin-3-ylamine (Klemm,L. H., Zell, R., Barnish, I. T., Klemm, R. A., J. Het. Chem, 1970,373-379) following the procedure of Example 67.

LRMS: m/Z 391 (M+1)⁺

Retention Time: 14 min*. *Chromatografic method B.

Example 1375-Acetyl-2-ethyl-4-[(6-fluoropyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

Obtained (65%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)one(Dal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) and6-fluoropyridin-3-ylamine (Rewcastle, G. W., Denny, W. A, Winters, R. T,J. Chem Soc, Perkin Trans. 1, 1996, 18, 2221-2226) following theprocedure of Example 67.

m.p. 183.1-184.3° C.

δ(CDCl3): 1.43 (t, 3H), 1.68 (s, 3H), 4.26 (q, 2H), 6.92 (dd, 1H), 7.42(m, 5H), 7.54 (m, 1H), 8.05 (d, 1H), 8.61 (s, 1H)

Example 1385-Acetyl-2-ethyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

Obtained (17%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and2-methylpyridin-3-ylamine (Nantka-Namirski, P., Kaczmarczyk, C., Toba,L., Acta Poloniae Pharmaceutica. 1967, 24(3), 231-237) following theprocedure of Example 63. The product was purified by columncromatography (silica gel, hexane/ethyl acetate 1:1).

m.p. 167.9-168.6° C.

δ(CDCl3): 1.42 (t, 3H), 1.64 (s, 3H), 2.60 (s, 3H), 4.27 (q, 2H), 7.18(m, 1H), 7.26 (m, 1H), 7.42 (m, 5H), 8.25 (s, 1H), 8.39 (m, 1H)

Example 1395-Acetyl-4-{[2-(dimethylamino)pyridin-3-yl]amino}-2-ethyl-6-phenylpyridazin-3(2H)-one

Obtained (20%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and3-amino-2-dimethylaminopyridine following the procedure of Example 63.The product was purified by column cromatography (silica gel,hexane/ethyl acetate 5:1).

m.p. 135.1-137.0° C.

δ(CDCl3): 1.42 (t, 3H), 1.64 (s, 3H), 2.93 (s, 6H), 4.31 (q, 2H), 6.88(m, 1H), 7.16 (m, 1H), 7.42 (m, 5H), 8.05 (m, 1H), 8.19 (m, 1H)

Example 1405-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridine-2-carboxylicacid

Obtained (43%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and5-aminopyridine-2-carboxylic add (De Waal, A., Hartog, A. F., De Jong,L., Biochimica et Biophysica Acta, 1988, 953(1), 20-25) following theprocedure of Example 67.

m.p. 226.1-226.8° C.

δ(DMSO-d6): 1.38 (m, 3H), 1.92 (s, 3H), 4.18 (q, 2H), 7.38 (m, 1H), 7.42(m, 5H), 7.86 (d, 1H), 8.42 (s, 1H), 9.38 (s, 1H), 12.92 (1H, s).

Example 1415-Acetyl-2-ethyl-4-[(2-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

Obtained (43%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and2-methoxypyridin-3-ylamine (Hwu, J. R., Wong, F. F., Shiao, M. J., J.Org. Chem, 1992, 57(19), 5254-5255) following the procedure of Example67.

m.p. 170.2-170.5° C.

δ(CDCl3): 1.42 (t, 3H), 1.68 (s, 3H), 3.98 (s, 3H), 4.29 (q, 2H), 6.86(m, 1H), 7.26 (m, 1H), 7.39 (m, 5H), 7.98 (m, 1H), 8.32 (s, 1H)

Example 1425-Acetyl-2-ethyl-4-(1H-indazol-4-ylamino)-6-phenylpyridazin-3(2H)-one

Obtained (83%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and1H-indazol-4-ylamine (Gamage, S. A.; Spicer, J. A; Rewcastle, G. W.;Milton, J.; J. Med. Chem., 2002, 45(3), 740-743) following the procedureof Example 67.

m.p. 217.8-219.0° C.

δ(CDCl3): 1.48 (t, 3H), 1.58 (s, 3H), 4.34 (q, 2H), 6.82 (dd, 1H), 7.35(m, 7H), 8.22 (s, 1H), 8.38 (s, 1H), 10.22 (s, 1H)

Example 1435-Acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one

Obtained (30%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and2-chloropyridin-3-ylamine following the procedure of Example 63. Theproduct was purified by column cromatography (silica gel, hexane/ethylacetate 2:1).

m.p. 153.0-153.6° C.

δ(CDCl3): 1.43 (t, 3H), 1.81 (s, 3H), 4.30 (q, 2H), 7.22 (m, 1H), 7.39(m, 6H), 8.45 (m, 1H), 8.2 (s, 1H)

Example 1445-Acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one

Obtained from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (DalPiaz, V et al, J. Med. Chem. 1997, 40, 1417) and5-chloropyridin-3-ylamine (Heindl, J., Kessler, H. J., DE2607012)following the procedure of Example 63. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 369 (M+1)⁺

Retention Time: 15.0 min*. *Chromatografic method B.

Example 1455-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinamide

Obtained (54%) from5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one. (Dal Piaz, V etal, J. Med. Chem. 1997, 40, 1417) and 5-amino-nicotinamide (Ueno, Y.Chemica Scripta 1984, 24(4-5), 185-7) following the procedure of Example67.

m.p. 235.8-236.8° C.

δ(CDCl3): 1.43 (t, 3H), 1.82 (s, 3H), 4.30 (q, 2H), 5.64 (s, 1H), 6.22(s, 1H), 7.41 (m, 5H), 7.73 (s, 1H), 8.55 (d, 1H), 8.69 (s, 1H), 8.76(d, 1H)

Example 1465-Acetyl-2-ethyl-4-(1,7-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one

Obtained from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (DalPiaz, V. et al, J. Med. Chem. 1997, 40, 1417) and[1,7]naphthyridin-8-ylamine (Van den Haak, H. J. W.; Van der Plas, H.C.; Van Veldhuizen, B. Journal of Heterocyclic Chemistry 1981, 18(7),1349-52.) following the procedure of Example 63. The product waspurified by preparative HPLC/MS.

LRMS: m/Z 386 (M+1)⁺

Retention Time: 10.0 min*. *Chromatografic method B.

Example 1472-Ethyl-5-glycoloyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

To a 0° C. stirred solution of potassium hydroxide (510 mg, 9 mmol) inmethanol (15 mL) a solution of the title compound of Example 138 (348mg, 1 mmol) was added dropwise within 10 min. Then, diacetoxyiodobenzene(644 mg, 2 mmol) was added portionwise and the final mixture was stirredat rt overnight. Solvent was removed under reduced pressure and theresidue was suspended in ethyl acetate and washed with saturated NH₄Clsolution and brine. The organic layer was dried and solvent was removedto yield a crude product that was purified by column chromathography(10% yield).

LRMS: m/Z 365 (M+1)⁺.

Retention Time: 13 min*. *Chromatografic method B.

Example 148 Methyl5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinate

Obtained (21%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and 5-aminonicotinicacid methyl esther (Jensen, H. H.; Lyngbye, L.; Jensen, A.; Bols, M.Chemistry—A European Journal 2002, 8(5), 1218-1226) following theprocedure of Example 63. The product was purified by preparativeHPLC/MS.

m.p. 144.6-145.8° C.

δ(CDCl3): 1.44 (t, 3H), 1.77 (s, 3H), 3.94 (s, 3H), 4.29 (q, 2H), 7.43(m, 5H), 7.92 (s, 1H), 8.54 (d, 1H), 8.85 (s, 1H), 9.05 (d, 1H)

Example 1495-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinicacid

Obtained from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (DalPiaz, V et al, J. Med. Chem. 1997, 40, 1417) and 5-aminonicotinic acid(Delarge, J. Pharmaceutica Acta Helvetiae (1969), 44(10), 637-43)following the procedure of Example 63. The product was purified bypreparative HPLC/MS.

LRMS: m/Z 379 (M+1)⁺

Retention Time: 12.0 min* *Chromatografic method B.

Example 1505-Acetyl-2-ethyl-4-(1,5-naphthyridin-3-ylamino)-6-phenylpyridazin-3(2H)-one

Obtained from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (DalPiaz, V et al, J. Med. Chem. 1997, 40, 1417) and[1,5]naphthyridin-3-ylamine (Czuba W., Akad, M., Wroclaw, P., RocnikiChemii, 1967, 41(2), 289-297) following the procedure of Example 63. Theproduct was purified by preparative HPLC/MS.

LRMS: m/Z 386 (M+1)⁺

Retention Time: 13.0 min*. *Chromatografic method B.

Example 1515-Acetyl-2-ethyl-4-[(8-hydroxy-1,7-naphthyridin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

Obtained (43%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and the title compoundof Preparation 67 following the procedure of Example 67.

m.p. 269.5-271.3° C.

δ(DMSO-d6): 1.35 (m, 3H), 1.48 (s, 3H), 4.19 (q, 2H), 7.44 (m, 6H), 8.59(s, 1H), 8.75 (d, 1H), 9.28 (s, 1H), 11.66 (s, 1H)

Example 1525-Acetyl-2-ethyl-6-phenyl-4-(thien-2-ylamino)pyridazin-3(2H)-one

To a solution of thiophen-2-ylcarbamic acid tert-butyl ester (157 mg,0.78 mmol) (Binder, D., Habison, G., Noe, C. R., Synthesis, 1977, 4,255-256) in ethyl ether (6.5 ml), 12N chlorhidric acid (2.8 mL) wasadded. The mixture was stirred for 30 min. and the solvent was removedto yield the deprotected thiophen-2-yl-ammonium chloride. Then asolution of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (150mg, 0.52 mmol) (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) inethanol (9 ml) and triethylamine (0.26 ml, 3.6 mmol) were added. Theresulting mixture was stirred at room temperature for 3 h. The finalproduct was collected by filtration and washed with diethylether toyield the title compound as a yellow solid (38%).

m.p. 182.6-183.5

δ(DMSO-d6): 1.33 (m, 3H), 1.62 (s, 3H), 4.16 (q, 2H), 6.73 (m, 1H), 6.82(m, 1H), 7.27 (m, 3H), 7.40 (m, 3H), 8.89 (s, 1H)

Example 1535-Acetyl-2-ethyl-6-phenyl-4-[(2-phenylpyridin-3-yl)amino]pyridazin-3(2H)-one

Obtained (46%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and2-phenylpyridin-3-ylamine (Miller, J. A, Farrell, R. P., TetrahedronLett., 1998, 39(36), 6441-6444) following the procedure of Example 67.

m.p. 181.8-182.4° C.

δ(DMSO-d6): 1.25 (m, 3H), 1.54 (s, 3H), 4.08 (q, 2H), 7.21 (m, 2H), 7.37(m, 7H), 7.67 (m, 3H), 8.48 (m, 1H), 8.95 (s, 1H)

Example 154 Ethyl{5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridin-2-yl}acetate

Obtained (30%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one(Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and5-aminopyridine-2-carboxylic acid ethyl ester (Cooper, G. H.; Rickard,R. L, J. Chem. Soc., 1971, 19, 3257-3260.) following the procedure ofExample 67.

LRMS: m/Z 421 (M+1)⁺

Retention Time: 14.0 min*. *Chromatografic method B.

Example 1555-Acetyl-2-ethyl-4-[(6-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of the title compound of Example 154 (77 mg, 0.18mmol) in 2 ml of ethanol, 1M NaOH solution (0.5 ml) was added and themixture was stirred at rt for 1 hour and at 60° C. for 1 h. Then it waslet to cool down, acidified to pH 6 and refluxed for 3 days. It was thebasified to pH 8 and extracted with dichloromethane. The organic layerwas finally washed with water and brine, dried and solvent was removedto yield the title product (20%).

LRMS: m/Z 349 (M+1)⁺.

Retention Time: 12 min*. *Chromatografic method B.

Example 156-162

-   156.    5-Acetyl-2-ethyl-4-[(6-hydroxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   157.    5-Acetyl-2-ethyl-4-[(2-fluoropyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   158.    5-Acetyl-4-[(6-chloro-4-methylpyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one-   159.    5-Acetyl-2-ethyl-4-[(3-hydroxypyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one-   160.    5-Acetyl-2-ethyl-4-[(4-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one-   161.    5-Acetyl-2-ethyl-4-(isoquinolin-8-ylamino)-6-phenylpyridazin-3(2H)-one-   162.    5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-7-ylamino)pyridazin-3(2H)-one

The title compounds were sinthesized from5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) and the corresponding amines following theproedure of example 67. The ESI/MS data and HPLC retention times aresummarized in Table 25.

TABLE 25 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 156 351 6.9157 353 8.3 158 383 9.0 159 351 8.5 160 365 6.5 161 385 6.5 162 385 9.6

Example 1635-Acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one

Obtained as a solid (54%) from the title compound of Preparation 36 and5-chloro pyridin-3-ylamine (Heindl, J.; Kessler, H. J. DE 2607012)following the procedure of Example 67.

m.p. 146.3-147.3° C.

δ(DMSO-d₃): 1.33 (t, 3H), 1.90 (s, 3H), 4.17 (q, 2H), 7.18 (m, 2H), 7.29(m, 1H), 7.46 (m, 1H), 7.56 (m, 1H), 8.27 (m, 2H), 9.25 (m, 1H).

Example 1645-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyridazin-3(2H)-one

Obtained as a solid (90%) from the title compound of Preparation 30 and2-methoxypyridin-3-ylamine (Hwu, J. R; Wong, F. F.; Shiao, M. J., J.Org. Chem., 1992, 57, 5254-5 following the procedure of Example 67.

m.p. 168.8-169.7° C.

δ(CDCl₃): 1.44 (t, 3H), 1.71 (s, 3H), 3.97 (s, 3H), 4.29 (q, 2H), 6.87(m, 1H), 7.10 (m, 2H), 7.27 (m, 1H), 7.39 (m, 2H), 8.00 (m, 1H), 8.22(s, 1H).

Examples 165-168

-   165.    5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   166.    5-Acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one-   167.    5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   168.    5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 30 and the corresponding pyridinylamines following theprocedure of Example 93. The ESI/MS data and HPLC retention times aresummarized in Table 26.

TABLE 26 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 165 367 7.4166 387 8.7 167 367 8.4 168 371 8.9

Example 1695-Acetyl-4-[2-chloropyridin-3-yl)amino]-2-(cyclopropylmethyl)-6-(4-fluorophenyl)pyridazin-3(2H)-one

Obtained as a solid (20%) from the title compound of Preparation 65 and2-chloropyridin-3-amine following the procedure of Example 67.

LRMS: m/Z 413 (M+1)⁺.

Retention Time: 16 min*. *Chromatografic method B. δ(CDCl₃): 0.47 (m,2H), 0.57 (m, 2H), 1.42 (m, 1H), 1.84 (s, 3H), 4.09 (d, 2H), 7.09 (m,2H), 7.22 (m, 1H), 7.41 (m, 3H), 8.21 (m, 1H), 8.63 (s, 1H).

Example 1705-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyridazin-3(2H)-one

Obtained as a solid (66%) from the title compound of Preparation 65 and2-methoxypyridin-3-ylamine (Hwu, J. R; Wong, F. F.; Shiao, M. J., J.Org. Chem., 1992, 57, 5254-5) following the procedure of Example 67.

m.p. 148.1-148.8° C.

δ(CDCl₃): 0.46 (m, 2H), 0.57 (m, 2H), 1.43 (m, 1H), 1.73 (s, 3H), 3.96(s, 3H), 4.10 (d, 2H), 6.85 (m, 1H), 7.09 (m, 2H), 7.27 (m, 1H), 7.38(m, 2H), 7.99 (m, 1H), 8.22 (s, 1H).

Example 1715-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one

Obtained as a solid (23%) from the title compound of Preparation 65 and2-methylpyridin-3-ylamine (Nantka-Namirski, P.; Kaczmarczyk, C.; Toba,L., Acta Poloniae Pharmaceutica 1967, 24, 231-7) following the procedureof Example 67.

LRMS: m/Z 393 (M+1)⁺.

Retention Time: 14 min*. *Chromatografic method B.

δ(CDCl₃): 0.50 (m, 2H), 0.58 (m, 2H), 1.43 (m, 1H), 1.65 (s, 3H), 2.57(s, 3H), 4.10 (d, 2H), 7.09 (m, 3H), 7.35 (m, 3H), 8.12 (s, 1H), 8.38(m, 1H).

Examples 172-174

-   172.    5-Acetyl-2-cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one-   173.    5-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   174.    5-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(pyridin-3-yl)    amino]pyridazin-3(2H)-one

The title compounds were synthesized from the title compound ofPreparation 65 and the corresponding pyridnylamines following theprocedure of Example 93. The ESI/MS data and HPLC retention times aresummarized in Table 27.

TABLE 27 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 172 397 9.2173 393 9.2 174 379 8.3

Examples 175-177

-   175.    5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one-   176.    5-Acetyl-6-(3-chlorophenyl)-4-[(2-chloropyridin-3-yl)amino]-2-ethylpyridazin-3(2H)-one-   177.    5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one

The title compounds were synthesized from5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (DalPiaz, V et al, J. Med. Chem. 1997, 40, 1417) and the correspondingpyridinylamines following the procedure of Example 93. The ESI/MS dataand HPLC retention times are summarized in Table 28.

TABLE 28 ESI/MS m/e Retention EXAMPLE (M + H)⁺ Time (min) 175 383 8.3176 404 9.3 177 383 9.1

Example 178 Methyl5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-8-carboxylate

A mixture of (160 mg, 0.556 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417), 5-aminoquinoline-8-carboxilic acid methylester (226 mg, 1.114 mmol) (Preparation 99) and ethanol (8 mL) wasintroduced in the microwave oven. The mixture was stirred at 126.0° C.during 45 minutes. The solvent was evaporated and the residue purifiedby column chromatography (silica gel, dichloromethane/methanol 100:1)and preparative HPLC/MS to yield the title compound (7 mg, 3% yield).

LRMS: m/Z 443 (M+1)⁺. Retention time: 13 min*. *Chromatografic method B

Example 1795-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one

A mixture of the title compound of Preparation 49 (2.0 g, 7.77 mmol),3-bromo-4-methylpyridine (1.8 ml, 15.5 mmol), anhydrous cuprous iodide(10.0 mg; 0.52 mmol) and potassium carbonate (1.60 g, 11.6 mmol) stirredat 145° C. for 12 h. It was let lo cool down and was partiotionedbetween ethyl acetate and water. The organic layer was wshed with waterand brine, dried and solvent was removed in vacuo. The solid thusobtained was thoroughly washed with warm ethyl ether and recrystallizedfrom methanol to yield the final product as a cream solid (0.97 g, 34%yield).

m.p. 215.9-216.3° C.

δ(DMSO-d₃): 1.18 (t, 3H), 1.28 (s, 3H), 2.05 (s, 3H), 4.04 (q, 2H), 7.15(m, 3H), 7.28 (m, 3H), 8.12 (m, 2H), 8.62 (s, 1H).

Example 1805-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methoxyphenyl)pyridazin-3(2H)-one

Obtained as a solid (13%) from the title compound of preparation 71 and4-bromoisoquinoline following the procedure of Example 101.

m.p. 210.8-212.7° C.

δ(DMSO-d₆): 1.28 (s, 3H), 1.37 (t, 3H), 3.7 (s, 3H), 4.2 (q, 2H), 6.9(d, 2H), 7.15 (d, 2H), 7.7 (t, 1H), 7.8 (t, 1H), 7.97 (d, 1H), 8.15 (d,1H), 8.29 (s, 1H), 9.17 (s, 1H).

Example 1815-Acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained as a solid (33%) from the title compound of Preparation 71 and3-bromopyridine following the procedure of Example 101.

m.p. 175.0-175.7° C.

δ(DMSO-d₆): 1.3 (t, 3H), 1.7 (s, 3H), 3.8 (s, 3H), 4.16 (q, 2H), 6.97(d, 2H), 7.23 (d, 2H), 7.27 (m, 1H), 7.43 (d, 1H), 8.27 (bs, 1H), 8.32(s, 1H), 9.04 (s, 1H, NH).

Example 1825-Acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

Obtained as a solid (15%) from the title compound of Preparation 71 and5-quinolylboronic acid following the procedure of Example 1.

m.p. 233.2-233.9° C.

δ(DMSO-d₆): 1.33 (s, 3H), 1.37 (t, 3H), 3.74 (s, 3H), 4.21 (q, 2H), 6.91(d, 2H), 7.16 (d, 2H), 7.35 (d, 1H), 7.55 (m, 1H), 7.60 (m, 1H), 7.86(d, 1H), 8.41 (d, 1H), 8.92 (m, 1H), 9.13 (s, 1H, NH).

Example 1835-Acetyl-2-ethyl-6-(4-methoxy-phenyl)-4-(1-oxy-quinolin-5-ylamino)--pyridazin-3(2H)-one

A solution of m-chloroperbenzoic acid (36.4 mg, 0.16 mmol) in drydichloromethane (1 mL) was added to a solution of the title compound ofExample 182 (70 mg, 0.16 mmol) in 2 mL of dichloromethane and themixture was stirred at RT under argon overnight. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (C-18 reverse phase Biotage® cartridge (water (0.1Mammonium acetate)/acetonitrile 99:1 to 1:99) to yield the title compoundas a solid (43 mg, 62% yield).

m.p. 259.7-261.3° C.

δ(DMSO-d₆): 1.37 (t, 3H), 1.43 (s, 3H), 3.75 (s, 3H), 4.20 (q, 2H), 6.94(d, 2H), 7.18 (d, 2H), 7.48 (m, 2H), 7.66 (t, 1H), 7.95 (d, 1H), 8.37(d, 1H), 8.61 (d, 1H), 9.19 (s, 1H, NH).

Example 1845-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methoxyphenyl)pyridazin-3(2H)-one

Obtained as a solid (24%) from the title compound of Preparation 75 and4-bromoisoquinoline following the procedure of Example 101.

m.p. 190.0-190.5° C.

δ(DMSO-d₆): 1.28 (s, 3H), 1.38 (t, 3H), 3.70 (s, 3H), 4.22 (q, 2H), 6.77(s, 1H), 6.79 (d, 1H), 6.95 (d, 1H), 7.28 (t, 1H), 7.71 (t, 1H), 7.82(t, 1H), 7.97 (d, 1H), 8.15 (d, 1H), 8.30 (s, 1H), 9.17 (s, 1H, NH),9.18 (s, 1H).

Example 1855-Acetyl-2-ethyl-6-(3-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained as a solid (33%) from the title compound of Preparation 75 and3-bromopyridine following the procedure of Example 101.

m.p. 152.7-153.8° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.73 (s, 3H), 3.75 (s, 3H), 4.16 (q, 2H), 6.85(m, 2H), 6.98 (d, 1H), 7.27-731 (m, 2H), 7.42 (d, 1H), 8.27 (m, 1H),8.32 (s, 1H), 9.08 (s, 1H, NH).

Example 1865-Acetyl-2-ethyl-6-(3-methoxyphenyl)-(quinolin-5-ylamino)pyridazin-3(2H)-one

Obtained as a solid (28%) from the title compound of Preparation 75 and5-quinolylboronic acid following the procedure of Example 1.

m.p. 194.3-195.8° C.

δ(DMSO-d₆): 1.32 (s, 3H), 1.37 (t, 3H), 3.70 (s, 3H), 4.21 (q, 2H), 6.77(s, 1H), 6.78 (d, 1H), 6.95 (d, 1H), 7.30 (t, 1H), 7.34 (d, 1H),7.54-7.63 (m, 2H), 7.86 (d, 1H), 8.42 (d, 1H), 8.92 (m, 1H), 9.18 (s,1H, NH).

Example 1875-Acetyl-2-ethyl-6-(3-methoxyphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one

Obtained as a yellow solid (58%) from the title compound of Example 186following the procedure of Example 183.

m.p. 215.5-216.1° C.

δ(DMSO-d₆): 1.37 (t, 3H), 1.43 (s, 3H), 3.71 (s, 3H), 4.21 (q, 2H), 6.80(s, 1H), 6.81 (d, 1H), 6.96 (d, 1H), 7.30 (t, 1H), 7.48 (m, 2H), 7.66(t, 1H), 7.95 (d, 1H), 8.37 (d, 1H), 8.61 (d, 1H), 9.24 (s, 1H, NH).

Example 1885-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methylphenyl)pyridazin-3(2H)-one

Obtained as a solid (18%) from the title compound of Preparation 79 and4-bromoisoquinoline following the procedure of Example 101.

m.p. 201.7-202.1° C.

δ(DMSO-d₆): 1.27 (s, 3H), 1.37 (t, 3H), 2.29 (s, 3H), 4.21 (q, 2H), 7.12(d, 2H), 7.17 (d, 2H), 7.72 (t, 1H), 7.82 (t, 1H), 7.97 (d, 1H), 8.15(d, 1H), 8.30 (s, 1H), 9.15 (s, 1H, NH), 9.17 (s, 1H).

Example 1895-Acetyl-2-ethyl-6-(4-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained as a solid (18%) from the title compound of Preparation 79 and3-bromopyridine following the procedure of Example 101.

m.p. 187.8-189.1° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.72 (s, 3H), 2.32 (s, 3H), 4.17 (q, 2H), 7.20(q, 4H), 7.27 (m, 1H), 7.43 (d, 1H), 8.26 (d, 1H), 8.32 (s, 1H), 9.05(s, 1H, NH).

Example 1905-Acetyl-2-ethyl-6-(4-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-(2H)-one

Obtained as a solid (40%) from the title compound of Preparation 79 and5-quinolylboronic acid following the procedure of Example 1.

LRMS (m/z): 399 (M+1)⁺.

Retention Time: 15 min*. *Chromatografic method B

m.p. 269.8-271.6° C.

Example 1915-Acetyl-2-ethyl-6-(4-methylphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one

Obtained as a solid (48%) from the title compound of Example 190following the procedure of Example 183.

m.p. 231.7-232.5° C.

δ(MeOH-d₄): 1.44 (t, 3H), 1.47 (s, 3H), 2.35 (s, 3H), 4.29 (q, 2H), 7.20(s, 4H), 7.52 (d, 1H), 7.6 (dd, 1H), 7.80 (t, 1H), 8.35 (d, 1H), 8.53(d, 1H), 8.72 (d, 1H).

Example 1925-Acetyl-2-ethyl-6-(4-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one

Obtained as a solid (9%) from the title compound of Preparation 79 and4-methyl-3-bromopyridine following the procedure of Example 101.

m.p. 196.1-197.3° C.

δ(DMSO-d₆): 1.34 (t, 3H), 1.43 (s, 3H), 2.22 (s, 3H), 2.31 (s, 3H), 4.17(q, 2H), 7.15 (d, 2H), 7.19 (d, 2H), 7.24 (d, 1H), 8.21 (s, 1H), 8.26(d, 1H), 8.72 (s, 1H, NH).

Example 1935-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methylphenyl)pyridazin-3(2H)-one

Obtained as a solid (27%) from the title compound of Preparation 83 and4-bromoisoquinoline following the procedure of Example 101.

Retention Time: 15 min*. *Chromatografic method B

δ(DMSO-d₆): 1.26 (s, 3H), 1.37 (t, 3H), 2.27 (s, 3H), 4.22 (q, 2H), 6.99(d, 1H), 7.07 (s, 1H), 7.18-7.26 (m, 2H), 7.72 (t, 1H), 7.82 (t, 1H),7.97 (d, 1H), 8.15 (d, 1H), 8.29 (s, 1H), 9.17 (s, 2H).

Example 1945-Acetyl-2-ethyl-6-(3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one

Obtained as a solid (21%) from the title compound of Preparation 83 and3-bromopyridine following the procedure of Example 101.

m.p. 134:9-136.1° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.72 (s, 3H), 2.32 (s, 3H), 4.17 (q, 2H), 7.06(d, 1H), 7.15 (s, 1H), 7.22-7.31 (m, 3H), 7.43 (dd, 1H), 8.26 (dd, 1H),8.32 (s, 1H), 9.08 (s, 1H, NH).

Example 1955-Acetyl-2-ethyl-6-(3-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

Obtained as a solid (25%) from the title compound of Preparation 83 and5-quinolylboronic acid following the procedure of Example 1.

LRMS (m/z): 399 (M+1)⁺.

Retention Time: 14 min*. *Chromatografic method B

m.p. 245.0-246.1° C.

Example 1965-acetyl-2-ethyl-6-(3-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one

Obtained as a solid (24%) from the title compound of Preparation 83 and4-methyl-3-bromopyridine following the procedure of Example 1.

m.p. 171.1-172.0° C.

δ(DMSO-d₆): 1.34 (t, 3H), 1.43 (s, 3H), 2.22 (s, 3H), 2.30 (s, 3H), 4.18(q, 2H), 7.02 (d, 1H), 7.10 (s, 1H), 7.20-7.28 (m, 3H), 8.21 (s, 1H),8.25 (d, 1H), 8.75 (s, 1H, NH).

Example 197 Methyl4-[4-acetyl-1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl]benzoate

Obtained as a solid (16%) from the title compound of Preparation 88 and4-bromoisoquinoline following the procedure of Example 101.

m.p. 182.9-183.6° C.

δ(DMSO-d₆): 1.28 (s, 3H), 1.36 (t, 3H), 3.82 (s, 3H), 4.20 (q, 2H), 7.37(d, 2H), 7.72 (t, 1H), 7.80 (t, 1H), 7.91 (d, 2H), 7.97 (d, 1H), 8.12(d, 1H), 8.27 (s, 1H), 9.14 (s, 1H), 9.22 (s, 1H, NH).

Example 198 Methyl4-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate

Obtained as a solid (15%) from the title compound of Preparation 88 and3-bromopyridine following the procedure of Example 101.

δ(DMSO-d₆): 1.3 (t, 3H), 1.7 (s, 3H), 3.82 (s, 3H), 4.20 (q, 2H), 7.27(m, 1H), 7.44 (d, 3H), 7.97 (d, 2H), 8.27 (d, 1H), 8.32 (s, 1H), 9.18(s, 1H, NH).

LRMS (m/z): 393 (M+1)⁺.

Retention Time: 13 min*. *Chromatografic method B

Example 1994-[4-Acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoicacid

Obtained as a solid (46%) from the title compound of Example 198following the procedure of Example 41.

m.p. 237.5-238.8° C.

δ(DMSO-d₆): 1.34 (t, 3H), 1.77 (s, 3H), 4.19 (q, 2H), 7.27 (m, 1H), 7.44(d, 3H), 7.95 (d, 2H), 8.27 (d, 1H), 8.32 (s, 1H), 9.16 (s, 1H, NH),13.09 (s, 1H; COOH).

Example 200 Methyl4-{4-acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}benzoate

Obtained as a solid (32%) from the title compound of Preparation 88 and4-methyl-3-bromopyridine following the procedure of Example 101.

m.p. 195.5-197.0° C.

δ(DMSO-d₆): 1.35 (t, 3H), 1.48 (s, 3H), 2.22 (s, 3H), 3.86 (s, 3H), 4.19(q, 2H), 7.24 (d, 1H), 7.43 (d, 2H), 7.96 (d, 2H), 8.22 (s, 1H), 8.25(d, 1H), 8.80 (s, 1H, NH).

Example 2014-{4-Acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}benzoicacid

Obtained as a solid (13%) from the title compound of Example 200following the procedure of Example 41.

m.p. 242.7-243.3° C.

δ(DMSO-d₆): 1.35 (t, 3H), 1.48 (s, 3H), 2.22 (s, 3H), 4.19 (q, 2H), 7.24(d, 1H), 7.40 (d, 2H), 7.96 (d, 2H), 8.22 (s, 1H), 8.25 (d, 1H), 8.80(s, 1H, NH).

Example 202 Methyl3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate

Obtained as a solid (20%) from the title compound of Preparation 93 and3-bromopyridine following the procedure of Example 101.

m.p. 148.8-150.2° C.

δ(MeOH-d₄): 1.33 (t, 3H), 1.68 (s, 3H), 3.82 (s, 3H), 4.19 (q, 2H), 7.27(m, 1H), 7.44-7.52 (m, 3H), 7.93 (s, 1H), 7.97 (d, 1H), 8.20 (dd, 1H),8.25 (s, 1H).

Example 2033-[4-Acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoicacid

Obtained as a solid (42%) from the title compound of Example 202following the procedure of Example 41.

m.p. 269.1-270.3° C.

δ(DMSO-d₆): 1.34 (t, 3H), 1.75 (s, 3H), 4.19 (q, 2H), 7.27 (m, 1H),7.44-7.51 (m, 2H), 7.54 (s, 1H), 7.89 (s, 1H), 7.97 (d, 1H), 8.27 (s,1H), 8.35 (s, 1H), 9.13 (s, 1H, NH), 13.13 (s, 1H, COOH).

Example 2045-Acetyl-4-[(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (12%) from the title compound of Preparation 16 and3-chloro fluoro-boronic acid following the procedure of Example 1.

m.p. 168.6-169.6° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.85 (s, 3H), 4.18 (q, 2H), 7.08 (m, 1H),7.29-7.35 (m, 4H), 8.60 (d, 2H), 9.19 (s, 1H, NH).

Example 2055-Acetyl-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one

Obtained as a solid (4%) from the title compound of Preparation 16 andan exces of 3-chloro-4-fluoro-boronic acid following the procedure ofExample 1.

m.p. 155.7-156.2° C.

δ(DMSO-d₆): 1.33 (t, 3H), 2.18 (s, 3H), 4.16 (q, 2H), 7.06 (m, 2H),7.31-7.41 (m, 6H), 8.65 (bs, 2H).

Example 2065-Acetyl-4-[(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one

Obtained as a solid (10%) from the title compound of Preparation 14 and3-chloro-4-fluoro-boronic acid following the procedure of Example 1.

m.p. 159.8-160.3° C.

δ(DMSO-d₆): 1.34 (t, 3H), 1.82 (s, 3H), 4.18 (q, 2H), 7.08 (m, 1H),7.29-7.35 (m, 3H), 7.43 (bs, 1H), 7.73 (d, 1H), 8.61 (bs, 1H), 9.18 (s,1H, NH).

Example 2075-Acetyl-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one

Obtained as a solid (11%) from the title compound of Preparation 14 and3-chloro-4-fluoro-boronic acid following the procedure of Example 1.

δ(DMSO-d₆): 1.33 (t, 3H), 2.14 (s, 3H), 4.16 (q, 2H), 7.06 (m, 2H),7.32-7.38 (m, 4H), 7.48 (bs, 1H), 7.80 (d, 1H), 8.61 (bs, 2H).

LRMS (m/z): 515 (M+1)⁺.

Retention Time: 18 min*. *Chromaotgrafic method B.

Example 208 Methyl[4-acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetate

Obtained as a solid (44%) from the title compound of Preparation 95 andquinoline-5-boronic acid following the procedure of Example 1.

m.p. 193.6-194.3° C.

δ(CDCl₃): 1.40 (s, 3H), 3.80 (s, 3H), 4.98 (S, 2H), 7.32 (m, 6H), 7.48(m, 1H), 7.62 (m, 1H), 8.06 (m, 1H), 8.41 (m, 2H), 8.98 (m, 1H).

Example 209[4-Acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]aceticacid

Obtained from the title compound of Example 208 following the procedureof Example 41.

LRMS: m/Z 415 (M+1)⁺.

Retention Time: 7.7 min

Example 2105-Acetyl-2-ethyl-4-[(3-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL),2-amino-3-methylpyridine (45 mg, 0.417 mmol) was added portionwise. Theresulting mixture was stirred at room temperature for five days. Thesolvent was evaporated and the residue purified by column chromatography(silica gel, hexane/ethyl acetate 2:1) to yield the title compound (26mg, 27% yield).

δ(DMSO-d₆): 1.35 (t, 3H), 1.80 (s, 3H), 2.32 (s, 3H), 4.22 (q, 2H), 6.95(m, 1H), 7.35 (m, 2H), 7.47 (m, 3H), 7.60 (d, 1H), 7.95 (d, 1H), 8.50(s, 1H).

Example 2115-Acetyl-2-ethyl-6-phenyl-4-(1H-pyrazol-3-ylamino)pyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL) under nitrogenatmosphere, 3-aminopyrazol (35 mg, 0.417 mmol) was added. The resultingmixture was stirred at room temperature during 30 minutes and the finalproduct was collected by filtration and washed with diethylether toyield the title compound (50 mg, 55.7% yield).

δ(DMSO-d₆): 1.29 (t, 3H), 1.55 (s, 3H), 4.15 (q, 2H), 5.73 (s, 1H), 7.14(s, 1H), 7.38-7.52 (m, 6H), 10.80 (s, 1H).

Example 2125-Acetyl-2-ethyl-6-phenyl-4-(9H-purin-6-ylamino)pyridazin-3(2H)-one

To a stirred solution of 250 mg (0.870 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (12 mL), adenine (235 mg, 1.740mmol) was added. The resulting mixture was stirred and refluxed duringtwo days. The solvent was evaporated and the residue purified by columnchromatography (silica gel, dichloromethane/methanol 95:5) andpreparative HPLC/MS to yield the title compound (4.4 mg, 1.4% yield).

LRMS: m/Z 376 (M+1)⁺.

Retention time: 7.5 min.

Example 2135-Acetyl-2-ethyl-4-[(3-methylisoxazol-5-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 200 mg (0.696 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (10 mL),5-amino-3-methylisoxazole (204 mg, 2.088 mmol) was added. The resultingmixture was stirred at 50° C. for four days. The solvent was evaporatedand the residue purified by column chromatography (silica gel,hexane/ethyl acetate 2:1) to yield the title compound (35 mg, 14.9%yield).

m.p. 177.6-178.7° C. δ(DMSO-d₆): 1.33 (t, 3H), 1.82 (s, 3H), 2.13 (s,3H), 4.19 (q, 2H), 5.71 (s, 1H), 7.34 (m, 2H), 7.47 (m, 3H), 10.02 (s,1H).

Example 2145-Acetyl-2-ethyl-4-[(8-hydroxyquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 5-amino-8-quinolinol(67 mg, 0.417 mmol) was added. The resulting mixture was stirred at roomtemperature during 40 hours and the final product was collected byfiltration and washed with diethylether to yield the title compound (100mg, 90% yield).

m.p. 261.9-262.6° C.

δ(DMSO-d₆): 1.25 (s, 3H), 1.37 (t, 3H), 4.20 (q, 2H), 6.90 (d, 1H),7.22-7.36 (m, 6H), 7.60 (m, 1H), 8.30 (d, 1H), 8.80 (m, 2H), 9.97 (s,1H).

Example 2155-Acetyl-2-ethyl-4-(1H-indazol-7-ylamino)-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 1H-indazol-7-amine (56mg, 0.417 mmol) was added. The resulting mixture was stirred at roomtemperature during one hour and the final product was collected byfiltration and washed with diethylether to yield the title compound (90mg, 86.5% yield).

m.p. 262.6-263.8° C.

δ(DMSO-d₆): 1.12 (s, 3H), 1.37 (t, 3H), 4.20 (q, 2H), 7.03 (m, 2H), 7.25(m, 2H), 7.38 (m, 3H), 7.57 (m, 1H), 8.06 (s, 1H), 9.04 (s, 1H),13.08(s, 1H).

Example 2165-Acetyl-4-[(6-bromoquinolin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.279 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL),8-amino-6-bromoquinoline (93 mg, 0.417 mmol) was added. The resultingmixture was stirred at room temperature or one day. The solvent wasevaporated and the residue purified by column chromatography (silicagel, hexane/ethyl acetate 3:1) to yield the title compound (110 mg,85.3% yield).

m.p. 146.8-147.5° C.

δ(DMSO-d₆): 1.35 (t, 3H), 1.76 (s, 3H), 4.21 (q, 2H), 7.27 (s, 1H),7.40-7.48 (m, 5H), 7.65 (m, 1H), 7.91 (s, 1H), 8.36 (d, 1H), 8.93 (m,1H), 9.36 (s, 1H).

Example 2175-Acetyl-2-ethyl-4-[(5-methylisoxazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethylnitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al., J. Med. Chem.1997, 40, 1417) in ethanol (4 mL), 3-amino-5-methylisoxazol (96 mg,0.978 mmol) was added. The resulting mixture was stirred, at roomtemperature for four days and the final product was collected byfiltration and washed with diethylether to yield the title compound (35mg, 37.2% yield).

m.p. 170.1-170.8° C.

δ(DMSO-d₆): 1.33 (t, 3H), 1.82 (s, 3H), 2.32 (s, 3H), 4.19 (q, 2H), 6.12(s, 1H), 7.32 (m, 2H), 7.45 (m, 3H), 9.36 (s, 1H).

Example 2185-Acetyl-2-ethyl-4-(isoxazol-3-ylamino)-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-aminoisoxazol (70 mg,0.834 mmol) was added. The resulting mixture was stirred at roomtemperature for four days and the final product was collected byfiltration and washed with diethylether to yield the title compound (58mg, 63.7% yield).

m.p. 176.4-177.1° C.

δ(DMSO-d₆): 1.34 (t, 3H), 1.84 (s, 3H), 4.20 (q, 2H), 6.43 (s, 1H), 7.32(m, 2H), 7.46 (m, 3H), 8.67 (s, 1H), 9.45 (s, 1H).

Example 2195-Acetyl-2-(cyclopropylmethyl)-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.319 mmol) of Preparation 97 inethanol (4 mL), 5-aminoquinoline (69 mg, 0.479 mmol) was added. Theresulting mixture was stirred at room temperature during one day and thefinal product was collected by filtration and washed with diethyletherto yield the title compound (53 mg, 40.4% yield).

m.p. 203.9-205.1° C.

δ(DMSO-d₆): 0.46 (m, 2H), 0.55 (m, 2H), 1.33 (m, 4H), 4.06 (q, 2H), 7.24(m, 2H), 7.35 (m, 4H), 7.58 (m, 2H), 7.86 (d, 1H), 8.44 (d, 1H), 8.93(m, 1H), 9.21 (s, 1H).

Example 2205-Acetyl-2-(cyclopropylmethyl)-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.319 mmol) of the title compound ofPreparation 97 in ethanol (4 mL), 8-aminoquinoline (69 mg, 0.479 mmol)was added. The resulting mixture was stirred at room temperature during22 hours. The solvent was evaporated and the residue purified by columnchromatography (silica gel, hexane/ethyl acetate 3:1) to yield the titlecompound (110 mg, 84.6% yield).

m.p. 123.1-124.7° C.

δ(DMSO-d₆): 0.45 (m, 2H), 0.53 (m, 2H), 1.30 (m, 1H), 1.61 (s, 3H), 4.05(q, 2H), 7.24 (d, 1H), 7.37-7.49 (m, 6H), 7.61 (m, 1H), 7.71 (d, 1H),8.40 (d, 1H), 8.93 (m, 1H), 9.35 (s, 1H).

Example 2215-Acetyl-2-ethyl-4-[(1-methyl-1H-pyrazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 80 mg (0.278 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-amino-1-methylpyrazol(40 mg, 0.417 mmol) was added. The resulting mixture was stirred at roomtemperature during three hours and the final product was collected byfiltration and washed with diethylether to yield the title compound (56mg, 59.6% yield).

m.p. 202.8-203.9° C.

δ(DMSO-d₆): 1.32 (t, 3H), 1.72 (s, 3H), 3.62 (s, 3H), 4.16 (q, 2H), 5.94(m, 1H), 7.29 (m, 2H), 7.43 (m, 3H), 7.52 (s, 1H), 8.84 (s, 1H).

Example 2225-Acetyl-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

A solution of the compound synthesized in Example 82 (210 mg, 0.546mmol) in dichloromethane (3 mL) was added dropwise to a cold solution of3-chloroperoxybenzoic acid (111 mg, 0.546 mmol) in dichloromethane (7mL). The mixture was stirred at room temperature for 27 hours and addedto a solution of KHSO₄ in water (20 mL, 25%). The organic layer waswashed with water, dried over sodium sulfate anhydride and evaporated.

The crude obtained was purified by column chromatography (silica gel,dichloromethane/methanol 110:5) to yield 160 mg (0.399 mmol) of thetitle compound (73%).

m.p. 264.0-264.8° C.

δ(DMSO-d₆): 1.37 (t, 3H), 1.41 (s, 3H), 4.21 (q, 2H), 7.26 (bs, 2H),7.39 (bs, 3H), 7.48 (m, 2H), 7.65 (m, 1H), 7.96 (d, 1H), 8.35 (d, 1H),8.61 (m, 1H), 9.24 (s, 1H).

Example 2235-Acetyl-2-ethyl-4-[(2-oxidoisoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

The title compound was synthesized from the title compound of Example 84following the procedure of Example 222. The crude obtained was purifiedby preparative HPLC/MS to yield the title compound (24% yield).

LRMS: m/Z 1401 (M+1)⁺. Retention time: 7.3 min.

Example 2245-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.311 mmol) of5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2M-one-(Dal Piaz,V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (5 mL);5-aminoquinoline (67 mg, 0.467 mmol) was added. The resulting mixturewas stirred at room temperature during two hours and the final productwas collected by filtration and washed with diethylether to yield thetitle compound (67 mg, 51.5% yield).

m.p. 186.2-186.9° C.

δ(DMSO-d₆): 1.37 (m, 6H), 4.22 (q, 2H), 7.17 (d, 1H), 7.33-7.45 (m, 4H),7.60 (m, 2H), 7.87 (d, 1H), 8.44 (d, 1H), 8.93 (m, 1H), 9.28 (s, 1H).

Example 225 5-Acetyl-6-(3-chlorophenyl)-2-ethyl4-(quinolin-8-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.311 mmol) of5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (DalPiaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL),8-aminoquinoline (67 mg, 0.467 mmol) was added. The resulting mixturewas stirred at room temperature for two hours. The solvent wasevaporated and the residue purified by column chromatography (silicagel, hexane/ethyl acetate 2:1) to yield the title compound (65 mg, 50%yield).

m.p. 127.0-127.7° C.

δ(DMSO-d₆): 1.36 (t, 3H), 1.65 (s, 3H), 4.22 (q, 2H), 7.27 (m, 2H),7.41-7.51 (m, 4H), 7.62 (m, 1H), 7.72 (d, 1H), 8.42 (d, 1H), 8.93 (m,1H), 9.36 (s, 1H).

Example 2265-Acetyl-2-ethyl-6-pyridin-4-yl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

The title compound was synthesized from the title compound ofPreparation 16 and the corresponding boronic acid following theprocedure of Example 1. The resulting residue was purified by columnchromatography (silica gel, dichloromethane/methanol 96:4) to yield thetitle compound (62.6% yield).

m.p. 214.0-215.5° C.

δ(DMSO-d₆): 1.38 (m, 6H), 4.23 (q, 2H), 7.26 (m, 2H), 7.34 (d, 1H), 7.58(m, 2H), 7.86 (d, 1H), 8.50 (d, 1H), 8.56 (m, 2H), 8.92 (m, 1H), 9.35(s, 1H).

Example 2275-Acetyl-2-ethyl-6-pyridin-3-yl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

The title compound was synthesized from the title compound ofPreparation 14 and the corresponding boronic acid following theprocedure of Example 1. The resulting residue was purified by columnchromatography (silica gel, dichloromethane/methanol 97:3) to yield thetitle compound (32% yield).

m.p. 180.7-181.6° C.

δ(DMSO-d₆): 1.38 (m, 6H), 4.23 (q, 2H), 7.33-7.41 (m, 2H), 7.56-7.67 (m,3H), 7.87 (d, 1H), 8.46 (m, 2H), 8.56 (m, 1H), 8.93 (m, 1H), 9.32 (s,1H).

Example 2285-Acetyl-2-ethyl-4-[(8-fluoroquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 150 mg (0.522 mmol) of5-acetyl-2-ethyl-4-nitro-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (8 mL),5-amino-8-fluoroquinoline (127 mg, 0.783 mmol) (Lee, Jae Keun et al.,Bull. Korean Chem. Soc., 1996, 17(1), 90) was added. The resultingmixture was stirred at room temperature for five hours. The solvent wasevaporated and the residue purified by column chromatography (silicagel, hexane/ethyl acetate 3:1) to yield the title compound (140 mg,66.7% yield).

m.p. 245.7-246-6° C.

δ(DMSO-d₆): 1.36 (m, 6H), 4.22 (q, 2H), 7.23 (m, 2H), 7.37-7.47 (m, 5H),7.70 (m, 1H), 8.43 (d, 1H), 8.99 (m, 1H), 9.16 (s, 1H).

Example 2295-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-(quinolin-8-ylamino)pyridazin-3(2H)-one

To a stirred solution of 150 mg (0.453 mmol) of the title compound ofPreparation 65 in ethanol (8 mL), 8-aminoquinoline (98 mg, 0.680 mmol)was added. The resulting mixture was stirred at room temperature duringfour hours and the final product was collected by filtration and washedwith diethylether to yield the title compound (115 mg, 59.3% yield).

m.p. 149.7-150.6° C.

δ(DMSO-d₆): 0.44 (m, 2H), 0.53 (m, 2H), 1.35 (m, 1H), 1.63 (s, 3H), 4.05(q, 2H), 7.27 (m, 3H), 7.38 (m, 2H), 7.45 (m, 1H), 7.61 (m, 1H), 7.70(d, 1H), 8.40 (d, 1H), 8.93 (m, 1H), 9.35 (s, 1H).

Example 2305-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-quinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 150 mg (0.491 mmol) of the title compound ofPreparation 30 in ethanol (8 mL), 5-aminoquinoline (106 mg, 0.737 mmol)was added. The resulting mixture was stirred at room temperature duringtwo hours and the final product was collected by filtration and washedwith diethylether to yield the title compound (140 mg, 70.7% yield).

m.p. 217.5-218.3° C.

δ(DMSO-d₆): 1.37 (m, 6H), 4.21 (q, 2H), 7.17-7.36 (m, 5H), 7.58 (m, 2H),7.87 (d, 1H), 8.43 (d, 1H), 8.92 (m, 1H), 9.23 (s, 1H).

Example 2315-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-(quinolin-8-ylamino)pyridazin-3(2H)-one

To a stirred solution of 150 mg (0.491 mmol) of the title compound ofPreparation 30 in ethanol (8 mL), 8-aminoquinoline (106 mg, 0.737 mmol)was added. The resulting mixture was stirred at room temperature duringone hour and the final product was collected by filtration and washedwith diethylether to yield the title compound (130 mg, 65.6% yield).

m.p. 153.5-154.3° C.

δ(DMSO-d₆): 1.36 (t, 3H), 1.62 (s, 3H), 4.21 (q, 2H), 7.26 (m, 3H),7.38-7.51 (m, 3H), 7.61 (m, 1H), 7.70 (d, 1H), 8.40 (d, 1H), 8.92 (m,1H), 9.35 (s, 1H).

Example 2325-Acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 150 mg (0.453 mmol) of the title compound ofPreparation 30 in ethanol (8 mL), 5-aminoquinoline (98 mg, 0.680 mmol)was added. The solvent was evaporated and the residue purified by columnchromatography (silica gel, hexane/ethyl acetate 1:1) to yield the titlecompound (174 mg, 89.7% yield).

m.p. 169.2-170.0° C.

δ(DMSO-d₆): 0.45 (m, 2H), 0.55 (m, 2H), 1.36 (m, 4H), 4.05 (q, 2H),7.18-7.37 (m, 5H), 7.55-7.64 (m, 2H), 7.87 (d, 1H), 8.43 (d, 1H), 0.92(m, 1H), 9.23 (s, 1H).

Example 2335-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one

The title compound was synthesized from the title compound of Example224 (390 mg, 0.931 mmol) following the procedure of Example 222. Thecrude obtained was purified by column chromatography (silica gel,dichloromethane/methanol 160:5) to yield the title compound (300 mg,74.1% yield).

m.p. 244.0-244.9° C.

δ(DMSO-d₆): 1.37 (t, 3H), 1.48 (s, 3H), 4.21 (q, 2H), 7.19 (d, 1H),7.35-7.52 (m, 5H), 7.66 (t, 1H), 7.96 (d, 1H), 8.36 (d, 1H), 8.61 (d,1H), 9.32 (s, 1H).

Example 2345-Acetyl-2-ethyl-4-[(2-methylquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one

To a stirred solution of 100 mg (0.348 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417) in ethanol (5 mL),5-amino-2-methylquinoline (83 mg, 0.522 mmol) was added. The resultingmixture was stirred at room temperature during three hours and the finalproduct was collected by filtration and washed with diethylether toyield the title compound (80 mg, 57.6% yield).

m.p. 204.5-205.1° C.

δ(DMSO-d₆): 1.30 (s, 3H), 1.37 (t, 3H), 2.66 (s, 3H), 4.21 (q, 2H), 7.25(m, 3H) 7.36 (m, 3H), 7.45 (d, 1H), 7.54 (t, 1H), 7.76 (d, 1H), 8.30 (d,1H), 9.16 (s, 1H).

Example 2355-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-(isoquinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 100 mg (0.311 mmol) of5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (DalPiaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL),5-amino-isoquinoline (67 mg, 0.467 mmol) was added. The resultingmixture was stirred at room temperature for two hours. The solvent wasevaporated and the residue purified by column chromatography (silicagel, hexane/ethyl acetate 1:2) to yield the title compound (28 mg, 21.5%yield).

m.p. 189.2-190.6° C.

δ(DMSO-d₆): 1.37 (m, 6H), 4.22 (q, 2H), 7.18 (d, 1H), 7.34-7.58 (m, 5H),7.86 (d, 1H), 7.99 (d, 1H), 8.54 (d, 1H), 9.25 (s, 1H), 9.33 (s, 1H).

Example 2365-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one

The title compound was synthesized from the title compound of Example230 (430 mg, 1.069 mmol) following the procedure of Example 222. Thecrude obtained was purified by column chromatography (silica gel,dichloromethane/methanol 110:5) to yield the title compound (360 mg,80.5% yield).

m.p. 245.1-246.0° C.

δ(DMSO-d₆): 1.37 (t, 3H), 1.44 (s, 3H), 4.21 (q, 2H), 7.20-7.31 (m, 4H),7.46-7.50 (m, 2H), 7.64 (m, 1H), 7.98 (d, 1H), 8.36 (d, 1H), 8.62 (d,1H), 9.28 (s, 1H).

Example 2375-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one

To a stirred solution of 400 mg (1.31 mmol) of the title compound ofPreparation 36 in ethanol (20 mL), 5-aminoquinoline (283 mg, 1.965 mmol)was added. The resulting mixture was stirred at room temperature duringtwo hours and the final product was collected by filtration and washedwith diethylether to yield the title compound (320 mg 60.7% yield).

m.p. 205.3-206.7° C.

δ(DMSO-d₆): 1.38 (m, 6H), 4.20 (q, 2H), 7.10 (m, 2H), 7.22 (m, 1H), 7.35(m, 2H), 7.60 (m, 2H), 7.85 (d, 1H), 8.42 (d, 1H), 8.95 (m, 1H), 9.25(s, 1H).

Example 2385-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one

The title compound was synthesized from the title compound of Example237 (200 mg, 0.497 mmol) following the procedure of Example 222. Thecrude obtained was purified by column chromatography (silica gel,dichloromethane/methanol 200:5) to yield the title compound (150 mg,72.1% yield).

m.p. 249.4-250.6° C.

δ(DMSO-d₆): 1.23 (t, 3H), 1.33 (s, 3H), 4.07 (q, 2H), 6.92-7.00 (m, 2H),7.11 (m, 1H), 7.25-7.38 (m, 3H), 7.51 (m, 1H), 7.82 (d, 1H), 8.22 (d,1H), 8.48 (d, 1H), 9.17 (s, 1H).

Example 2395-[(5-Actyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-carboxylicacid

A mixture of (160 mg, 0.556 mmol) of5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al,J. Med. Chem. 1997, 40, 1417), 5-aminoquinoline-8-carboxilic acid (210mg, 1.114 mmol) (Breckenridge, J. G. et al. Canadian J. of ResearchSect. B, 1947, 25, 49) and ethanol (8 mL) was introduced in themicrowave. The mixture was stirred at 120° C. during 45 minutes. Thesolvent was evaporated and the residue purified by column chromatography(silica gel, dichloromethane/methanol 300:1) to yield the title compound(50 mg, 41.7% yield).

LRMS: m/Z 429 (M+1)⁺. Retention time: 14 min*. *Chromatografic method B

The following examples illustrate pharmaceutical compositions accordingto the present invention.

COMPOSITION EXAMPLES Composition Example 1

Preparation of Tablets

Formulation:

Compound of the present invention 5.0 mg Lactose 113.6 mgMicrocrystalline cellulose 28.4 mg Light silicic anhydride 1.5 mgMagnesium stearate 1.5 mg

Using a mixer machine, 15 g of the compound of the present invention aremixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose.The mixture is subjected to compression moulding using a rollercompactor to give a flake-like compressed material. The flake-likecompressed material is pulverised using a hammer mill, and thepulverised material is screened through a 20 mesh screen. A 4.5 gportion of light silicic anhydride and 4.5 g of magnesium stearate areadded to the screened material and mixed. The mixed product is subjectedto a tablet making machine equipped with a die/punch system of 7.5 mm indiameter, thereby obtaining 3,000 tablets each having 150 mg in weight.

Composition Example 2

Preparation of Coated Tablets

Formulation:

Compound of the present invention 5.0 mg Lactose 95.2 mg  Corn starch40.8 mg  Polyvinylpyrrolidone K25 7.5 mg Magnesium stearate 1.5 mgHydroxypropylcellulose 2.3 mg Polyethylene glycol 6000 0.4 mg Titaniumdioxide 1.1 mg Purified talc 0.7 mg

Using a fluidised bed granulating machine, 15 g of the compound of thepresent invention are mixed with 285.6 g of lactose and 122.4 g of cornstarch. Separately, 22.5 g of polyvinylpyrrolidone is dissolved in 127.5g of water to prepare a binding solution. Using a fluidised bedgranulating machine, the binding solution is sprayed on the abovemixture to give granulates. A 4.5 g portion of magnesium stearate isadded to the obtained granulates and mixed. The obtained mixture issubjected to a tablet making machine equipped with a die/punch biconcavesystem of 6.5 mm in diameter, thereby obtaining 3,000 tablets, eachhaving 150 mg in weight.

Separately, a coating solution is prepared by suspending 6.9 g ofhydroxypropylmethyl-cellulose 2910, 1.2 g of polyethylene glycol 6000,3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water.Using a High Coated, the 3,000 tablets prepared above are coated withthe coating solution to give film-coated tablets, each having 154.5 mgin weight.

Composition Example 3

Preparation of Capsules

Formulation:

Compound of the present invention 5.0 mg Lactose monohydrate 200 mgColloidal silicon dioxide 2 mg Corn starch 20 mg Magnesium stearate 4 mg

25 g of active compound, 1 Kg of lactose monohydrate, 10 g of colloidalsilicon dioxide, 100 g of corn starch and 20 g of magnesium stearate aremixed. The mixture is sieved through a 60 mesh sieve, and then filledinto 5,000 gelatine capsules.

Composition Example 4

Preparation of a Cream

Formulation:

Compound of the present invention 1% Cetyl alcohol 3% Stearyl alcohol 4%Gliceryl monostearate 4% Sorbitan monostearate 0.8%   Sorbitanmonostearate POE 0.8%   Liquid vaseline 5% Methylparaben 0.18%  Propylparaben 0.02%   Glycerine 15%  Purified water csp. 100% 

An oil-in-water emulsion cream is prepared with the ingredients listedabove, using conventional methods.

1. A pyridazin-3(2H)-one derivative compound of formula (I):

wherein R¹ and R² represent independently from each other: a hydrogenatom; a group chosen from acyl, hydroxycarbonyl, alkoxycarbonyl,carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; an alkyl, alkenyl oralkynyl group, wherein said alkyl, alkenyl or alkynyl group isoptionally substituted by one or more substituents chosen from halogenatoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoylgroups; an aryl or heteroaryl group, wherein said aryl or heteroarylgroup is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, amino,nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl, mono- anddi-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; a saturated or unsaturated heterocyclic group,which is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, oxo,amino, nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl,mono- and di-alkylcarbamoyl, difluoromethyl, trifluoromethyl,difluoromethoxy and trifluoromethoxy groups; a group of formula—(CH₂)_(n)—R⁶ wherein n is an integer from 0 to 4 and R⁶ represents: acycloalkyl or cycloalkenyl group; an aryl group, which is optionallysubstituted by one or more substituents chosen from halogen atoms,alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- anddi-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; or a 3- to 7-membered ring having from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulphur, which ring isoptionally substituted by one or more substituents chosen from halogenatoms, alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- anddi-alkylamino, nitro, cyano and trifluoromethyl groups; R³ represents amonocyclic or polycyclic aryl or heteroaryl group, which is optionallysubstituted by one or more substituents chosen from: halogen atoms;alkyl and alkylene groups, which are optionally substituted by one ormore substituents chosen from halogen atoms; phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; phenyl, hydroxy, hydroxyalkyl,alkoxy, cycloalkoxy, nitro, aryloxy, alkylthio, alkylsulphinyl,alkylsulphonyl, alkylsulfamoyl, acyl, amino, mono- and di-alkylamino,acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- anddi-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido,alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano,difluoromethoxy and trifluoromethoxy groups; R⁵ represents a group—COOR⁷ or a monocyclic or polycyclic aryl or heteroaryl group,whereinsaid —COOR⁷ or monocyclic or polycyclic aryl or heteroaryl group isoptionally substituted by one or more substituents chosen from: halogenatoms; alkyl and alkenyl groups, which are optionally substituted by oneor more substituents chosen from halogen atoms, phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; and phenyl, hydroxy,alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsuiphinyl,alkylsuiphonyl, alkylsulfamoyl, amino, mono- and di-alkylamino,acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, ureido, N′-alkylureido,N′,N′-dialkylureido, alkylsuiphamido, aminosuphonyl, mono- anddi-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxygroups; wherein R⁷ represents an alkyl, which is optionally substitutedby one or more substituents chosen from halogen atoms, hydroxy, alkoxy,aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino,hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoylgroups, and a group of formula—(CH₂)_(n)—R⁶ wherein n and R⁶ are as defined above; and R⁴ represents:a hydrogen atom; a hydroxy, alkoxy, amino, mono- or di-alkylamino group;an alkyl, alkenyl or alkynyl group, wherein said alkyl, alkenyl oralkynyl group is optionally substituted by one or more substituentschosen from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo,amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl,alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; or agroup of formula—(CH₂)_(n)—R⁶ wherein n and R⁶ are as defined above or a N-oxideobtainable from heteroaryl radicals present in the structure when saidheteroradical comprise at least one N atom or a pharmaceuticallyacceptable salt thereof; with the proviso that when R⁵ is neither anoptionally substituted heteroaryl group nor a group COOR⁷, R³ is anoptionally substituted heteroaryl group.
 2. A compound according toclaim 1 wherein R² represents a hydrogen atom or an aryl group, which isoptionally substituted by one or more substituents chosen from halogenatoms, nitro, C₁-C₄ alkoxy, C₁-C₄ hydroxyalkyl and CO₂—(C₁-C₄ alkyl)groups.
 3. A compound according to claim 2, wherein R² is a hydrogenatom or a phenyl group, which is unsubstitued or substituted with 1 or 2unsubstituted substituents chosen from fluorine atoms, chlorine atoms,and nitro, C₁-C₄ hydroxyalkyl and —CO₂—(C₁-C₄alkyl) groups.
 4. Acompound according to claim 1, wherein R¹ represents a group chosenfrom: a (C₁-C₄) alkyl group, which is optionally substituted by one ormore hydroxy groups; and groups of formula—(CH₂)_(n)—R⁶ wherein n is an integer from 1 to 3 and R⁶ represents a(C₃-C₆) cycloalkyl group.
 5. A compound according to claim 4, wherein R¹is an unsubstituted C₁-C₄ alkyl, an unsubstituted C₁-C₄ hydroxyalkyl oran unsubstituted cyclopropyl-(C₁-C₄ alkyl)— group.
 6. A compoundaccording to claim 1, wherein R³ represents a monocyclic or polycyclicaryl or heteroaryl group, wherein said monocyclic or polycyclic aryl orheteroaryl group is optionally substituted by one or more substituentschosen from: halogen atoms; alkyl and alkylene groups, wherein saidalkyl and alkylene groups are optionally substituted by one or moresubstituents chosen from halogen atoms; phenyl, hydroxy,hydroxycarbonyl, hydroxyalkyl, alkoxycarbonyl, alkoxy, cycloalkoxy,nitro, aryloxy, alkylthio, alkylsuiphinyl, alkylsuiphonyl,alkylsulfamoyl, acyl, amino, mono- or di-alkylamino, acylamino,hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl,ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsuiphamido,aminosuphonyl, mono- and di-alkylaminosuiphonyl, cyano, difluoromethoxyand trifluoromethoxy groups.
 7. A compound according to claim 6, whereinR³ represents a group chosen from monocyclic or polycyclic aryl orheteroaryl groups, wherein said monocyclic or polycyclic aryl orheteroaryl groups are optionally substituted by one or more substituentschosen from: halogen atoms; (C₁-C₄) alkyl groups, which are optionallysubstituted by one or more hydroxy groups; and (C₁-C₄) alkoxy, nitro,hydroxy, hydroxycarbonyl, carbamoyl, (C₁-C₄ alkoxy)-carbonyl and cyanogroups.
 8. A compound according to claim 7, wherein R³ represents aphenyl group, a naphthyl group or a 5- to 14-membered monocylic orpolycyclic heteroaryl group containing 1, 2 or 3 heteroatoms chosen fromN, O and S, the phenyl, naphthyl and heteroaryl groups beingunsubstituted or substituted with 1 or 2 unsubstituted substituentschosen from: halogen atoms; C₁-C₄ alkyl and C₁-C₄ hydroxyalkyl groups;and C₁-C₄ alkoxy, nitro, hydroxy, hydroxycarbonyl, carbamoyl, (C₁-C₄alkoxy)-carbonyl and cyano groups.
 9. A compound according to claim 8wherein R³ represents a phenyl group, a naphtyl group or a substitutedor unsubtituted heteroaryl group chosen from substituted orunsubstituted oxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl,thiazolyl, thiadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl,indolyl, benzoxazolyl, naphthyridinyl, benzofuranyl, pyrazinyl,pyrimidinyl and pyrrolopyridyl radicals.
 10. A compound according toclaim 1, wherein R⁴ represents: an unsubstituted mono-(C₁-C₄ alkyl)aminoor unsubstituted di-(C₁-C₄ alkyl)amino group; a C₁-C₄ alkyl group whichis unsubstituted or substituted by one or more substituents chosen fromhydroxy, C₁-C₄ alkoxy, amino, mono-(C₁-C₄ alkyl)amino and di-(C₁-C₄alkyl)amino groups; an unsubstituted phenyl-(C₁-C₄ alkyl)— group; or agroup of formula—(CH₂)_(n)—R⁶ wherein n is 2 and R⁶ represents a radical chosen fromphenyl, pyridyl and thienyl, optionally substituted by one or moresubstituents chosen from halogen atoms, alkyl, hydroxy, alkoxy,alkylenedioxy, amino, mono- and di-alkylamino, nitro, ciano andtrifluoromethyl groups.
 11. A compound according to claim 10 wherein R⁴represents an alkyl group having from 1 to 6 carbon atoms and which isoptionally substituted by one or more substituents chosen from halogenatoms and hydroxy groups.
 12. A compound according to claim 1, whereinR⁵ represents a group COOR⁷ or a monocyclic or polycyclic aryl orheteroaryl group, wherein said —COOR⁷ or monocyclic or polycyclic arylor heteroaryl group is optionally substituted by one or moresubstituents chosen from halogen atoms, C₁-C₄ alkyl groups, C₁-C₄alkoxycarbonyl groups, hydroxycarbonyl groups and C₁-C₄ alkoxy groups.13. A compound according to claim 12, wherein R⁵ represents a groupCOOR⁷ or a monocyclic or polycyclic aryl or heteroaryl group, whereinsaid COOR⁷ or a monocyclic or polycyclic aryl or heteroaryl group isoptionally substituted by one or more substituents chosen from halogenatoms and C₁-C₄ alkoxy groups.
 14. A compound according to claim 12,wherein R⁵ represents —CO₂R⁷, wherein R⁷ represents an unsubstitutedC₁-C₄ alkyl group, or R⁵ represents a phenyl group or a 5- to 10-membered monocyclic or polycyclic heteroaryl group containing 1 or 2heteroatoms chosen from N, O and S, the phenyl and heteroaryl groupsbeing unsubstituted or substituted by 1 or 2 substituents chosen fromC₁-C₄ alkoxy groups and halogen atoms.
 15. A compound according to claim14, wherein R⁵ represents a phenyl group, or a substituted orunsubtituted heteroaryl group chosen from substituted or unsubstitutedoxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl,thiadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl,benzoxazolyl, naphthyridinyl, benzofuranyl, pyrazinyl, pyrimidinyl andpyrrolopyridyl radicals.
 16. A pyridazin-3(2H)-one derivative compoundof formula (I):

wherein R¹ and R² represent independently from each other: a hydrogenatom; a group chosen from acyl, hydroxycarbonyl, alkoxycarbonyl,carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; an alkyl, alkenyl oralkynyl group, wherein said alkyl, alkenyl or alkynyl group isoptionally substituted by one or more substituents chosen from halogenatoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoylgroups; an aryl or heteroaryl group, wherein said aryl or heteroarytgroup is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, amino,nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl, mono- anddi-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; a saturated or unsaturated heterocyclic group,which is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, oxo,amino, nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl,mono- and di-alkylcarbamoyl, difluoromethyl, trifluoromethyl,diftuoromethoxy and trifluoromethoxy groups; a group of formula—(CH₂)_(n)—R⁶ wherein n is an integer from 0 to 4 and R⁶ represents: acycloalkyl or cycloalkenyl group; an aryl group, which is optionallysubstituted by one or more substituents chosen from halogen atoms,alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- anddi-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; or a 3- to 7-membered ring having from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulphur, which ring isoptionally substituted by one or more substituents chosen from halogenatoms, alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- anddi-alkylamino, nitro, cyano and trifluoromethyl groups; R³ represents amonocyclic or polycyclic aryl or heteroaryl group, which is optionallysubstituted by one or more substituents chosen from: halogen atoms;alkyl and alkylene groups, which are optionally substituted by one ormore substituents chosen from halogen atoms; phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; phenyl, hydroxy, hydroxyalkyl,alkoxy, cycloalkoxy, nitro, aryloxy, alkylthio, alkylsulphinyl,alkylsulphonyl, alkylsulfamoyl, acyl, amino, mono- and di- alkylamino,acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- anddi-alkylcarbamoyl, ureido, N′-alkylureido, N′, N′-dialkylureido,alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano,difluoromethoxy and trifluoromethoxy groups; R⁵ represents a group—COOR⁷ or a monocyclic or polycyclic aryl or heteroaryl group,whereinsaid —COOR⁷ or monocyclic or polycyclic aryl or heteroaryl group isoptionally substituted by one or more substituents chosen from: halogenatoms; alkyl and alkenyl groups, which are optionally substituted by oneor more substituents chosen from halogen atoms, phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; and phenyl, hydroxy,alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsuiphinyl,alkylsulphonyl, alkylsulfamoyl, amino, mono- and di-alkylamino,acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, ureido, N′-alkylureido,N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- anddi-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxygroups; R⁷ represents an alkyl, which is optionally substituted by oneor more substituents chosen from halogen atoms, hydroxy, alkoxy,aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino,hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoylgroups, and a group of formula—(CH₂)_(n)—R⁶ wherein n and R⁶are as defined above; and R⁴ represents: ahydrogen atom; a hydroxy, alkoxy, amino, mono- or di-alkylamino group;an alkyl, alkenyl or alkynyl group, wherein said alkyl, alkenyl oralkynyl group is optionally substituted by one or more substituentschosen from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo,amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl,alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; or agroup of formula—(CH₂)_(n)—R⁶ wherein n and R⁶ are as defined above or a N-oxideobtainable from heteroaryl radicals present in the structure when saidheteroradical comprise at least one N atom or a pharmaceuticallyacceptable salt thereof with the proviso that when R⁵ is neither anoptionally substituted heteroaryl group nor a group COOR⁷, R³ is anoptionally substituted heteroaryl group; wherein when R⁵ represents apolycyclic heteroaryl group, R⁵ represents a group of formula (XXIII):

wherein Y represents an O atom, a S atom or an —NH— group, n is 0, 1 or2 and each R is the same or different and is a C₁-C₄ alkoxy group or ahalogen atom.
 17. A compound as claimed in claim 1, chosen from:5-acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(3,5-dichlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-3-ylpyridazin-3(2H)-one;methyl4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amin]benzoate;5-acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-3-ylpyridazin-3(2H)-one;3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;3-{[5-acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile;methyl4-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl]amino}benzoate;5-acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-2-ylpyridazin-3(2H)-one;3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one;3-{[5-acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile;5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-2-ylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyridin-2-ylpyridazin-3(2H)-one;3-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile;5-acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one;5-acetyl-4-[(3,5-dichlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one;5-acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-2-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;methyl4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoate;5-acetyl-2-ethyl-4-[(2-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one;4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoicacid;5-acetyl-2-(cyclopropylmethyl)-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;3-{[5-acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile;5-acetyl-2-(cyclopropylmethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;3-{[5-acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzonitrile;5-acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[bis-(4-methoxycarbonylphenyl)-amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-{bis[4-(hydroxymethyl)phenyl]amino}-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-nitrophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3,5-dichlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(4-methoxycarbonylphenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one5-acetyl-4-[(3,5-dichloropyridin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(pyrazin-2-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(pyrimidin-2-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(5-nitropyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1 h-indol-4-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-4-(1,3-benzothiazol-6-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(thianthren-1-ylamino)pyridazin-3(2H)-one;methyl3-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylate;5-acetyl-2-ethyl-4-[(4-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(1h-1,2,4-triazol-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(6-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(2H-indazol-5-ylamino)-6-phenylpyridazin-3(2H)-one;methyl4-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-3-carboxylate;5-acetyl-2-ethyl-6-phenyl-4-(pyridin-2-ylamino)pyridazin-3(2H)-one;3-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylicacid;5-acetyl-2-ethyl-4-[(3-methylcinnolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-methylquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1h-indol-5-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-5-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(6-methoxyquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(5-bromoquinolin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(4-methylpyrimidin-2-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-(cyclopropylmethyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-6-(3-fluorophenyl)-2-isopropyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-6-(1h-benzimidazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one;5-acetyl-6-(1,3-benzoxazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one;5-acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one;5-acetyl-6-benzooxazol-2-yl-4-[bis-(3-chlorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one;5-acetyl-6-benzooxazol-2-yl-4-[bis-(3-fluorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one;3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzamide;5-acetyl-2-ethyl-4-(isoquinolin-1-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(2-butylquinazolin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-4-(1,2-benzisothiazol-3-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(pyridin-4-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-hydroxy-7h-purin-6-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(quinazolin-4-ylamino)pyridazin-3(2H)-one;5-acetyl-4-[(4-chloro-1H-indazol-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(7-chloroquinolin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(4,6-dichloropyrimidin-2-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(6-hydroxy-2H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-methylquinolin-4-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1H-imidazol-2-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(quinolin-4-ylamino)pyridazin-3(2H)-one;5-acetyl-4-(cinnolin-4-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-d]pyrimidin-4-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1H-indazol-6-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-(6-methoxypyridin-3-yl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-thien-3-ylpyridazin-3(2H)-one;5-acetyl-6-(1-benzofuran-5-yl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one;1-ethyl-5-[(3-methoxyphenyl)amino]-n,n-dimethyl-6-oxo-3-pyridin-3-yl-1,6-dihydropyridazine-4-carboxamide;5-[(3-chlorophenyl)amino]-1-ethyl-n-methyl-6-oxo-3-pyridin-4-yl-1,6-dihydropyridazine-4-carboxamide;2-ethyl-4-[(3-fluorophenyl)amino]-5-glycoloyl-6-pyridin-4-ylpyridazin-3(2H)-one;2-ethyl-4-[(3-fluorophenyl)amino]-5-(methoxyacetyl)-6-pyridin-3-ylpyridazin-3(2H)-one;5-[(dimethylamino)acetyl]-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;2-ethyl-4-[(3-fluorophenyl)amino]-5-[(methylamino)acetyl]-6-pyridin-4-ylpyridazin-3(2H)-one;3-{[2-ethyl-3-oxo-5-(3-phenylpropanoyl)-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl]amino}benzamide;ethyl4-acetyl-5-[(3-chlorophenyl)amino]-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate;ethyl4-acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate;5-acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-[(3-methoxyphenyl)amino]pyridazin-3(2H)-one;5-acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1,6-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(5-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-pyridin-4-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-pyridin-4-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-pyridin-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one;4-[(5-acetyl-2-ethyl-3-oxo-6-thien-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;5-acetyl-2-ethyl-6-thien-2-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one;5-Acetyl-4-(bis(4-cyanophenyl)amino)-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-4-(quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(quinolin-5-ylamino)-6-thien-3-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-3-ylpyridazin-3(2H)-one;4-[(5-acetyl-2-ethyl-3-oxo-6-thien-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;5-acetyl-2-ethyl-6-thien-3-yl-4-[(3,4,5-trifluorophenyl)amino]pyridazin-3(2H)-one;2-ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;2-ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;2-ethyl-4-(isoquinolin-4-ylamino)-6-phenyl-5-(3-phenylpropanoyl)pyridazin-3(2H)-one;2-ethyl-6-phenyl-4-(quinolin-5-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one;2-ethyl-6-phenyl-4-(pyridin-3-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one;5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(1H-imidazo[4,5-b]pyridin-2-yl)pyridazin-3(2H)-one;5-acetyl-6-(1,3-benzothiazol-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one;5-acetyl-6-(1-benzofuran-2-yl)-4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-pyridin-3-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzoicacid;5-acetyl-2-ethyl-4-[(1-oxidopyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;ethyl3-(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-ylamino)benzoate;3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzamide;5-acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-b]pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(6-fluoropyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-4-{[2-(dimethylamino)pyridin-3-yl]amino}-2-ethyl-6-phenylpyridazin-3(2H)-one;5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridine-2-carboxylicacid;5-acetyl-2-ethyl-4-[(2-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1H-indazol-4-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinamide;5-acetyl-2-ethyl-4-(1,7-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one;2-ethyl-5-glycoloyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;methyl5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinate;5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinicacid;5-acetyl-2-ethyl-4-(1,5-naphthyridin-3-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(8-hydroxy-1,7-naphthyridin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(thien-2-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-[(2-phenylpyridin-3-yl)amino]pyridazin-3(2H)-one;ethyl{5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridin-2-yl}acetate;5-acetyl-2-ethyl-4-[(6-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(6-hydroxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-fluoropyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(6-chloro-4-methylpyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(3-hydroxypyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(4-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-8-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(quinolin-7-ylamino)pyridazin-3(2H)-one;5-acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-4-[(2-chloropyridin-3-yl)amino]-2-(cyclopropylmethyl)-6-(4-fluorophenyl)pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(pyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-4-[(2-chloropyridin-3-yl)amino]-2-ethylpyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;methyl5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-8-carboxylate;5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methoxyphenyl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methoxy-phenyl)-4-(1-oxy-quinolin-5-ylamino)-2H-pyridazin-3-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methoxyphenyl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methylphenyl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methylphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methylphenyl)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;methyl4-[4-acetyl-1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl]benzoate;methyl4-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate;4-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoicacid; methyl4-{4-acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}benzoate;4-{4-acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}benzoicacid; methyl3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate;3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoicacid;5-acetyl-4-[(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;5-acetyl-4-[(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;5-acetyl-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one;methyl[4-acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetate;[4-acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]aceticacid;5-acetyl-2-ethyl-4-[(3-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(1H-pyrazol-3-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-phenyl-4-(9H-purin-6-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(3-methylisoxazol-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(8-hydroxyquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(1H-indazol-7-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-4-[(6-bromoquinolin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(5-methylisoxazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-(isoxazol-3-ylamino)-6-phenylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(1-methyl-1H-pyrazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-oxidoisoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-pyridin-4-yl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-pyridin-3-yl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(8-fluoroquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-(quinolin-8-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-(quinolin-8-ylamino)pyridazin-3(2H)-one;5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-4-[(2-methylquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(isoquinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one;and5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-8-carboxylicacid; and pharmaceutically acceptable salts thereof.
 18. A compound asclaimed in claim 17, chosen from:5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-3-ylpyridazin-3(2H)-one;5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;4-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino]benzoicacid;5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one;5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-phenyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(1H-indol-4-ylamino)-6-phenylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one;5-Acetyl-6-(3-fluorophenyl)-2-isopropyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-(cyclopropylmethyl)-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(isoquinolin-5-ylamino)-6-phenylpyridazin-3(2H)-one;5-Acetyl-6-(1,3-benzoxazol-2-yl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-phenylpyridazin-3(2H)-one;2-Ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methylphenyl)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-4-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(4-methylphenyl)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]quinoline-8-carboxylicacid;5-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;Methyl3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate;5-acetyl-2-ethyl-6-(3-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-3-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one;3-(4-Acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoicacid methyl ester;5-Acetyl-2-ethyl-6-(3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-(3-fluorophenyl)-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one;5-Acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-pyridin-3-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;5-Acetyl-2-ethyl-6-(4-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-one;and5-Acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-b]pyridin-3-ylamino)pyridazin-3(2H)-one.19. A process for the preparation of a compound of formula (XXIV):

wherein R¹ and R² represent independently from each other: a hydrogenatom; a group chosen from acyl, hydroxycarbonyl, alkoxycarbonyl,carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; an alkyl, alkenyl oralkynyl group, wherein said alkyl, alkenyl or alkynyl group isoptionally substituted by one or more substituents chosen from halogenatoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoylgroups; an aryl or heteroaryl group, wherein said aryl or heteroarylgroup is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, amino,nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl, mono- anddi-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; a saturated or unsaturated heterocyclic group,which is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, oxo,amino, nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl,mono- and di-alkylcarbamoyl, difluoromethyl, trifluoromethyl,difluoromethoxy and trifluoromethoxy groups; a group of formula—(CH₂)_(n)—R⁶ wherein n is an integer from 0 to 4 and R⁶ represents: acycloalkyl or cycloalkenyl group; an aryl group, which is optionallysubstituted by one or more substituents chosen from halogen atoms,alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- anddi-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; or a 3- to 7-membe red ring having from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulphur, which ring isoptionally substituted by one or more substituents chosen from halogenatoms, alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- anddi-alkylamino, nitro, cyano and trifluoromethyl groups; R³ represents amonocyclic or polycyclic aryl or heteroaryl group, which is optionallysubstituted by one or more substituents chosen from: halogen atoms;alkyl and alkylene groups, which are optionally substituted by one ormore substituents chosen from halogen atoms; phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; phenyl, hydroxy, hydroxyalkyl,alkoxy, cycloalkoxy, nitro, aryloxy, alkylthio, alkylsulphinyl,alkylsulphonyl, alkylsulfamoyl, acyl, amino, mono- and di- alkylamino,acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- anddi-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido,alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano,difluoromethoxy and trifluoromethoxy groups; and R⁴ represents: ahydrogen atom; a hydroxy, alkoxy, amino, mono- or di-alkylamino group;an alkyl, alkenyl or alkynyl group, wherein said alkyl, alkenyl oralkynyl group is optionally substituted by one or more substituentschosen from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo,amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl,alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; or agroup of formula—(CH₂)_(n)—R⁶ wherein n and R⁶are as defined above wherein each G₁, G₂,G₃ and G₄ independently represents a nitrogen or carbon atom, Yrepresents an 0 atom, a S atom or an —NH— group and the benzene ring mayoptionally be substituted by one or more substituents, which processcomprises reacting a carboxylic acid ester of formula (VII)

wherein R¹, R², R³ and R⁴ are as defined above, with an ortho-subtitutedaniline of formula (VIII) in the presence of a dehydrating agent,

wherein each G₁, G₂, G₃ and G₄ independently represent a nitrogen orcarbon atom and Y represents an amino, mercapto or hydroxy group.
 20. Acompound of formula (XXV)

wherein M² is either a hydrogen atom or a group R² and M³ is either ahydrogen atom or a group R³, and wherein R¹ and R² representindependently from each other: a hydrogen atom; a group chosen fromacyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl anddialkylcarbamoyl; an alkyl, alkenyl or alkynyl group, wherein saidalkyl, alkenyl or alkynyl group is optionally substituted by one or moresubstituents chosen from halogen atoms, hydroxy, alkoxy, aryloxy,alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl andmono- and di-alkylcarbamoyt groups; an aryl or heteroaryl group, whereinsaid aryl or heteroaryl group is optionally substituted by one or moresubstituents chosen from halogen atoms, hydroxy, hydroxyalkyl,hydroxycarbonyl, alkoxy, alkylenedioxy, alkoxyacyl, aryloxy, acyl,acyloxy, alkylthio, amino, nitro, cyano, mono- and di-alkylamino,acylamino, carbamoyl, mono- and di-alkylcarbamoyl, difluoromethyl,trifluoromethyl, difluoromethoxy and trifluoromethoxy groups; asaturated or unsaturated heterocyclic group, which is optionallysubstituted by one or more substituents chosen from halogen atoms,hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy, alkylenedioxy,alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, oxo, amino, nitro, cyano,mono- and di-alkylamino, acylamino, carbamoyl, mono- anddi-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; a group of formula—(CH₂)_(n)—R⁶ wherein n is an integer from 0 to 4 and R⁶ represents: acycloalkyl or cycloalkenyl group; an aryl group, which is optionallysubstituted by one or more substituents chosen from halogen atoms,alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- anddi-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; or a 3- to 7-membered ring having from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulphur, which ring isoptionally substituted by one or more substituents chosen from halogenatoms, alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- anddi-alkylamino, nitro, cyano and trifluoromethyl groups; R³ represents amonocyclic or polycyclic aryl or heteroaryl group, which is optionallysubstituted by one or more substituents chosen from: halogen atoms;alkyl and alkylene groups, which are optionally substituted by one ormore substituents chosen from halogen atoms; phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; phenyl, hydroxy, hydroxyalkyl,alkoxy, cycloalkoxy, nitro, aryloxy, alkylthio, alkylsulphinyl,alkylsulphonyl, alkylsulfamoyl, acyl, amino, mono- and di-alkylamino,acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- anddi-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido,alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano,difluoromethoxy and trifluoromethoxy groups; R⁵ represents a group—COOR⁷ or a monocyclic or polycyclic aryl or heteroaryl group,whereinsaid —COOR⁷ or monocyclic or polycyclic aryl or heteroaryl group isoptionally substituted by one or more substituents chosen from: halogenatoms; alkyl and alkenyl groups, which are optionally substituted by oneor more substituents chosen from halogen atoms, phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; and phenyl, hydroxy,alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsuiphinyl,alkylsuiphonyl, alkylsulfamoyl, amino, mono- and di-alkylamino,acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, ureido, N′-alkylureido,N′,N′-dialkylureido, alkylsuiphamido, aminosuphonyl, mono- anddi-alkylaminosuiphonyl, cyano, difluoromethoxy and trifluoromethoxygroups; wherein R⁷ represents an alkyl, which is optionally substitutedby one or more substituents chosen from halogen atoms, hydroxy, alkoxy,aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino,hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoylgroups, and a group of formula—(CH₂)_(n)—R⁶ and R⁴ represents: a hydrogen atom; a hydroxy, alkoxy,amino, mono- or di-alkylamino group; an alkyl, alkenyl or alkynyl group,wherein said alkyl, alkenyl or alkynyl group is optionally substitutedby one or more substituents chosen from halogen atoms, hydroxy, alkoxy,aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino,hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- anddi-alkylcarbamoyl groups; or a group of formula—(CH₂)_(n)—R⁶ where n and R⁶ are as defined above.
 21. A compoundaccording to claim 20, which is ethyl4-acetyl-5-amino-1-ethyl-6-oxo-1,6-dehydropyridazine-3-carboxylate. 22.A pharmaceutical composition comprising a compound as claimed in claim1, mixe with a pharmaceutically acceptable diluent or carrier.
 23. Amethod for treating a subject afflicted with a pathological condition ordisease susceptible to amelioration by inhibition of phosphodiesterase4, which method comprises administering to the said subject an effectiveamount of a compound as claimed in claim 1, wherein the pathologicalcondition or disease is chosen from asthma and atopic dermatitis.
 24. Acomposition comprising: (i) a pyridazin-3(2H)-one derivative compound offormula (I):

wherein R¹ and R² represent independently from each other: a hydrogenatom; a group chosen from acyl, hydroxycarbonyl, alkoxycarbonyl,carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; an alkyl, alkenyl oralkynyl group, wherein said alkyl, alkenyl or alkynyl group isoptionally substituted by one or more substituents chosen from halogenatoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoylgroups; an aryl or heteroaryl group, wherein said aryl or heteroarylgroup is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, amino,nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl, mono- anddi-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; a saturated or unsaturated heterocyclic group,which is optionally substituted by one or more substituents chosen fromhalogen atoms, hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy,alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio, oxo,amino, nitro, cyano, mono- and di-alkylamino, acylamino, carbamoyl,mono- and di-alkylcarbamoyl, difluoromethyl, trifluoromethyl,difluoromethoxy and trifluoromethoxy groups; a group of formula—(CH₂)_(n)—R⁶ wherein n is an integer from 0 to 4 and R⁶ represents: acycloalkyl or cycloalkenyl group; an aryl group, which is optionallysubstituted by one or more substituents chosen from halogen atoms,alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- anddi-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy andtrifluoromethoxy groups; or a 3- to 7-membered ring having from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulphur, which ring isoptionally substituted by one or more substituents chosen from halogenatoms, alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- anddi-alkylamino, nitro, cyano and trifluoromethyl groups; R³ represents amonocyclic or polycyclic aryl or heteroaryl group, which is optionallysubstituted by one or more substituents chosen from: halogen atoms;alkyl and alkylene groups, which are optionally substituted by one ormore substituents chosen from halogen atoms; phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; phenyl, hydroxy, hydroxyalkyl,alkoxy, cycloalkoxy, nitro, aryloxy, alkylthio, alkylsuiphinyl,alkylsulphonyl, alkylsulfamoyl, acyl, amino, mono- and di-alkylamino,acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- anddi-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido,alkylsuiphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano,difluoromethoxy and trifluoromethoxy groups; R⁵ represents a group—COOR⁷ or a monocyclic or polycyclic aryl or heteroaryl group,whereinsaid —COOR⁷ or monocyclic or polycyclic aryl or heteroaryl group isoptionally substituted by one or more substituents chosen from: halogenatoms; alkyl and alkenyl groups, which are optionally substituted by oneor more substituents chosen from halogen atoms, phenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, alkylthio, oxo, amino, mono- anddi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,and mono- and di-alkylcarbamoyl groups; and phenyl, hydroxy,alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl,alkylsuiphonyl, alkylsulfamoyl, amino, mono- and di-alkylamino,acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl,mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsuiphamido, aminosuphonyl, mono- anddi-alkylaminosu Iphonyl, cyano, difluoromethoxy and trifluoromethoxygroups; wherein R⁷ represents an alkyl, which is optionally substitutedby one or more substituents chosen from halogen atoms, hydroxy, alkoxy,aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino,hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoylgroups, and a group of formula—(CH₂)_(n)—R⁶ wherein n and R⁶are as defined above; and R⁴ represents: ahydrogen atom; a hydroxy, alkoxy, amino, mono- or di-alkylamino group;an alkyl, alkenyl or alkynyl group, wherein said alkyl, alkenyl oralkynyl group is optionally substituted by one or more substituentschosen from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, oxo,amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl,alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups; or agroup of formula—(CH₂)_(n)—R⁶ wherein n and R⁶ are as defined above or a N-oxideobtainable from heteroaryl radicals present in the structure when saidheteroradical comprise at least one N atom or a pharmaceuticallyacceptable salt thereof; with the proviso that when R⁵ is neither anoptionally substituted heteroaryl group nor a group COOR⁷, R³ is anoptionally substituted heteroaryl group; and (ii)another compound chosenfrom (a) steroids, (b) immunosuppressive agents, (c) T-cell receptorblockers and (d) antiinflammatory drugs.
 25. A compound according toclaim 14, wherein the phenyl and heteroaryl groups are unsubstituted orsubstituted by 1 or 2 substituents selected from C₁-C₄ alkoxy groups,chlorine atoms and fluorine atoms.
 26. A method for treating a subjectafflicted with a pathological condition or disease susceptible toamelioration by inhibition of phosphodiesterase 4, which methodcomprises administering to the said subject an effective amount of acompound as claimed in claim 1, wherein the pathological condition ordisease is psoriasis.